The purpose of this study is to evaluate the efficacy and safety of paliperidone palmitate as compared with placebo in the treatment of participants with schizophrenia (psychiatric disorder with symptoms of emotional instability, detachment from reality, often with delusions [a false belief held in the face of strong differing evidence, especially as a symptom of psychiatric disorder] and hallucinations [imagining things], and withdrawal into the self).

This is a randomized (the study drug is assigned by chance), double-blind (neither physician nor participant knows the name of the assigned drug), placebo-controlled (an inactive substance; a pretend treatment [with no drug in it] that is compared in a clinical trial with a drug to test if the drug has a real effect), parallel-group (comparing the response in two groups of participants receiving different treatments), fixed-dose, multi-center (when more than one hospital or medical school team work on a medical research study) study of paliperidone palmitate in participants with schizophrenia. The study will consist of 3 periods: an up to 2-week pre-observation (screening) period, a double-blind period from Day 1 (baseline) to Week 13 (end of double-blind period) assessment, and a post-observation period starting after the Week 13 assessment to Week 21. For participants who discontinue the study before the last assessment in Week 13, the post-observation period will start after the discontinuation from double-blind period assessment with follow-up visits at 4, 8, and 12 weeks after the last injection. After completion of the double-blind period (Week 13), discontinuation of double-blind period treatment or withdrawal from the study, participants may receive treatment consistent with the usual standard of care. The total duration of the study will be 21 weeks, including the double-blind and post-observation periods. Participants will be randomly assigned to 1 of 2 treatment groups in a 1:1 ratio (intramuscular injections of either paliperidone palmitate or matching placebo). Injections of paliperidone palmitate or placebo will be given at Day 1 and at Weeks 1, 5, and 9 by a study drug manager and/or injector. For those participants receiving paliperidone palmitate, the Day 1 injection will be 150 milligram equivalent (mg eq.) paliperidone palmitate, followed by 100 mg eq. injections of paliperidone palmitate at Week 1, and 75 mg eq. injections of paliperidone palmitate at Weeks 5 and 9. Participants randomly assigned to placebo will receive injections matching the paliperidone palmitate injections on the same days. Efficacy will be assessed using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression - Severity (CGI-S). Participant's safety will be monitored throughout the study.

Inclusion Criteria:

• Participants meeting Diagnostic criteria for schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision
• Women had to be: postmenopausal (for at least 2 years), surgically sterile (had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (as judged by the investigator; per local regulations), or if sexually active, be practicing a highly effective method of birth control (eg, prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method [eg, condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel], male partner sterilization) as local regulations permitted, before entry, and had to agree to continue to use the same method of contraception throughout the study
• A Positive and Negative Syndrome Scale (PANSS) total score at screening and at baseline (Day 1) of 60 to 120
• Documented history of exposure to either a risperidone formulation or a paliperidone formulation and known to be tolerated before baseline (Day 1) (Even if the participant's experience of taking risperidone or paliperidone cannot be confirmed at the time of informed consent, the participant will be able to meet this criterion if the participant takes oral risperidone 2 mg/day or more or paliperidone ER 6 mg/day or more for at least 4 days between the day of informed consent and the day before baseline, and it is possible to confirm that there is no lack of tolerability in the participant)
• Women of childbearing potential must have a negative beta human chorionic gonadotropin pregnancy test at the screening urine pregnancy test

Exclusion Criteria:

• Primary active Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision Axis I diagnosis other than schizophrenia
• A Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis of active substance dependence within 3 months before screening (nicotine and caffeine are not exclusionary)
• Relevant history or current presence of any significant or unstable cardiovascular, respiratory, neurological (including seizures or significant cerebrovascular), renal, hepatic, hematologic, endocrine, immunologic, or other systemic disease
• History or current presence of neuroleptic malignant syndrome or tardive dyskinesia
• Known or suspected hypersensitivity or intolerance to risperidone, paliperidone, Intralipid, or any of their excipients (including egg yolks, soybean oil, phospholipids, and glycerol)