Inclusion Criteria:

Registration: Patients having both diffuse and follicular architectural elements will be considered eligible if the histology is predominantly follicular (≥ 50% of the cross-sectional area), and there is no evidence of transformation to a large cell histology.

• Biopsy-proven diagnosis of Grade 1 or 2 follicular non-Hodgkin's lymphoma with no evidence of transformation to large cell histology.
• Meet criteria for Low Tumor Burden:
  • No nodal or extra nodal mass ≥ 7 centimeter (cm)
  • <3 nodal masses >3 cm in diameter
  • No systemic symptoms or B symptoms
  • No splenomegaly >16 cm by CT scan
  • No risk of compression of a vital organ.
  • No leukemic phase with >5000/mm³ circulating lymphocytes.
• No cytopenias defined as:
  • Platelets <100,000/mm³
  • Hemoglobin (Hgb) <10 g/dL
  • Absolute Neutrophil Count (ANC) <1500/mm³
• Must have Stage III or Stage IV disease.
• Baseline measurements/evaluations obtained within 6 weeks of registration. Patient must have at least one objective measurable disease parameter.
• Age ≥ 18 years.
• Eastern Oncology Cooperative Group Performance Status 0-1.
• Must not have received investigational agents within 30 days of registration.
• Signed Institutional Review Board (IRB)-approved informed consent.
• Willing to provide blood samples for research purposes.
• Women must not be pregnant or breastfeeding.
• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception.
• No prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
• No prior treatment with cytotoxic drugs or rituximab for a previous cancer or another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody.
• No prior use of any monoclonal antibody within 3 months of randomization.
• No history of severe allergic/anaphylactic reactions to humanized/murine monoclonal antibodies or known sensitivity/allergy to murine products.
• No history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least 2 years and did not require treatment with cytotoxic drugs or rituximab.
• No major surgery within 4 weeks prior to randomization, other than for diagnosis.
• Must be Human Immunodeficiency Virus (HIV) negative.
• Have adequate organ function without growth factor and/or transfusion support within ≤ 2 weeks prior to registration:
  • ANC ≥ 1500/mm³
  • Hgb ≥ 10 g/dL
  • Platelets ≥ 100,000/mm³
  • Serum Creatinine ≤ 2x Upper Limit Normal (ULN)
  • Total Bilirubin ≤ 2x ULN
  • AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 5x ULN
  • PTT (Partial Thromboplastin Time) or aPTT (activated Partial Thromboplastin Time) >1.5x the ULN in the absence of a lupus anticoagulant
  • INR (International Normalized Ratio) >1.5x the ULN in the absence of therapeutic anticoagulation
• No active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics).
• Must not receive immunization with attenuated live vaccines within 28 days prior to registration or during the study period.
• Must be tested for hepatitis B surface antigen (HBsAg) and total hepatitis B core antibody (anti-HBc) within 2 weeks of registration. Patients who are chronic carriers of HBsAg and anti-HBc are excluded.
• Must be tested for hepatitis C antibody within 2 week of registration. If this test is positive, patients are excluded unless a hepatitis C virus ribonucleic acid (HCV RNA) is negative.
• No evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (i.e., severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease.