Purpose The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 (¹³¹I) –tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma. Patients and Methods Patients received six cycles of CVP followed by one cycle of tositumomab and ¹³¹I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety. Results All 30 patients enrolled completed CVP as well as tositumomab and ¹³¹I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (≥ 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade ≥ 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia. Conclusion These mature data demonstrate that sequential therapy with a non-anthracycline–containing regimen comprising CVP followed by one cycle of tositumomab and ¹³¹I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.