This is a Phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with PPMS. The study will enroll approximately 435 subjects at up to 60 sites in the United States and Canada.

Inclusion Criteria:

• Definitive diagnosis of PPMS
• Disease duration of ≥ 1 year
• EDSS at baseline between 2.0 and 6.5 points, inclusive
• Score of ≥ 2.0 on the Functional Systems (FS) scale for the pyramidal system or gait that is due to lower extremity findings
• Presence of at least one of the following in a CSF specimen obtained during the screening period and analyzed by the central laboratory or results from a CSF sample obtained during the previous 24 months:
• For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, vaginal ring, intrauterine device, physical barrier) during study treatment and for 1 year following the last dose of study drug

Exclusion Criteria:

• Pregnancy or lactation
• Incompatibility with MRI
• Lack of peripheral venous access
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
• Known active bacterial, viral, fungal, mycobacterial, or other infection (including atypical mycobacterial disease, but excluding fungal infections of nail beds or recurrent herpes zoster or simplex infections) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 30 days prior to screening or oral antibiotics within 14 days prior to screening
• History or presence of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis)
• History of cancer, including solid tumors and hematologic malignancies (except resected and fully resolved cutaneous basal cell and squamous cell carcinomas)
• History of alcohol or drug abuse within 6 months prior to screening
• History of or currently active primary or secondary immunodeficiency
• Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
• Presence of other significant, uncontrolled cardiovascular, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease that might interfere with a subject's ability to participate and to complete approximately 2.5 years of study participation
• History or presence of MS relapse or exacerbation
• History or presence of vascular disease potentially affecting the brain or spinal cord (e.g., stroke, transient ischemic attack, carotid stenosis, aortic aneurysm, intracranial aneurysm, hemorrhage, arteriovenous malformation)
• History or presence of myelopathy due to spinal cord compression by disk or vertebral disease
• History of severe, clinically significant central nervous system trauma (e.g., cerebral contusion, spinal cord compression)
• History of intracranial or intraspinal tumor (e.g., meningioma, glioma)
• History or presence of potential metabolic cause of myelopathy or encephalopathy (e.g., vitamin B12 deficiency, thyroid abnormalities)
• History or presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, human T-cell lymphotropic virus type 1 [HTLV-1], or herpes zoster myelopathy)
• History of genetically inherited progressive CNS degenerative disorder (e.g., X-linked adrenoleukodystrophy, hereditary spastic paraparesis)
• Neuromyelitis optica
• History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, Sj�gren syndrome, Beh�et disease)
• History or presence of sarcoidosis
• Previous treatment with rituximab (MabThera(R)/Rituxan(R))
• Previous treatment with lymphocyte-depleting therapies (e.g., cyclophosphamide, Campath(R), anti-CD4, cladribine, total body irradiation, bone marrow transplantation), except mitoxantrone, which should not be used 12 months prior to randomization
• Treatment with an investigational agent within 90 days or 5 half-lives of the investigational drug (whichever is longer) prior to randomization
• Receipt of a live vaccine within 30 days prior to randomization
• Systemic corticosteroid therapy within 30 days prior to randomization
• Treatment with IFN-β, glatiramer acetate, IVIg, or plasmapheresis within 60 days prior to randomization
• Treatment with non-lymphocyte-depleting immunosuppressive therapies (e.g., azathioprine, mycophenolate mofetil [MMF], cyclosporine) within 90 days prior to randomization
• Statins or hormone replacement therapy started within 30 days prior to randomization

Intent-to-Treat (ITT) Population: All randomized participants, with groups defined by treatment assigned at randomization.

Up to 122 weeks (from start of first infusion until study completion or early termination)