The purpose of this study is to determine whether pralatrexate, given with vitamin B12 and folic acid, is effective in the treatment of relapsed or refractory B-cell Non-Hodgkin's lymphoma (NHL). The study will also investigate the safety of pralatrexate with vitamin B12 and folic acid in this participant population. Additionally, this study includes the collection of blood samples to investigate the pharmacokinetics (PK) of pralatrexate in this participant population (PK is the activity of a drug in the body over a period of time, including how the drug is absorbed, distributed in the body, localized in the tissues, and excreted from the body).

Inclusion Criteria:

• Histologically/cytologically confirmed, measurable (lesion or node =2 cm by CT [at least 1 cm if by spiral CT]) B-cell Non-Hodgkin's Lymphoma, using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification
• Progressive or persistent disease after ≥ 1 prior treatment(s)
• Recovered from toxic effects of prior treatment
• At least 4 weeks since most recent cytotoxic therapy
• Easter Cooperative Oncology Group (ECOG) performance status ≤ 2
• Adequate blood, liver, and kidney functions as defined by laboratory levels
• 1.0 mg/day orally of folic acid for at least 7 days prior & 1 mg intramuscular of vitamin B12 within 10 weeks of the planned start of pralatrexate
• Females of childbearing potential must agree to use medically acceptable birth control from start of pralatrexate until at least 30 days after the last administration of pralatrexate and must have a negative serum pregnancy test within 14 days prior to the first day of study treatment
• Males who are not surgically sterile must agree to use medically acceptable birth control from start of pralatrexate until at least 90 days after the last administration of pralatrexate
• Available for repeat dosing and follow-up
• Able to give written informed consent

Exclusion Criteria:

• Relapsed participants with diffuse large B-cell lymphoma (DLBCL) who are candidates for high-dose therapy and autologous stem cell transplantation (SCT) and for whom high-dose therapy and autologous SCT is a standard curative option
• Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancies other than those exceptions listed above, the participant must be disease-free for ≥ 5 years. Participants with other prior malignancies < 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease
• Congestive heart failure Class III/IV according to the New York Heart Association Functional Classification
• Uncontrolled hypertension
• Known human immunodeficiency virus (HIV)-positive diagnosis
• Symptomatic central nervous system (CNS) metastases or lesions for which treatment is required. Participants who received prophylactic CNS treatment are eligible.
• Participants who have undergone an allogeneic SCT
• Participants who have relapsed < 100 days from the time of an autologous SCT
• Participants with disease refractory to peripheral blood SCT or who have relapsed < 100 days from the time of transplant
• Active uncontrolled infection, underlying medical condition, or other serious illness that would impair the ability of the participant to receive protocol treatment.
• Major surgery within 14 days of enrollment
• Receipt of any conventional chemotherapy or radiation therapy (encompassing a substantial [> 10%] amount of bone marrow) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study treatment or planned use during the course of the study
• Receipt of systemic corticosteroids within 1 week of study treatment, unless participant has been taking a continuous dose of no more than 10 mg/day of prednisone or its equivalent for at least 1 month
• Use of any investigational drugs, biologics, or devices within 4 weeks prior to study treatment or planned use during the course of the study
• Previous exposure to pralatrexate
• Females who are pregnant or breastfeeding