Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with shortcourse chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment. Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [18 F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging. Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CTand PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P = 0.010). Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.After three decades with little advance in the outcome for patients with follicular lymphoma (FL), the addition of the anti-CD20 chimeric monoclonal antibody, rituximab, dramatically changed the overall response rates (ORR) and may be affecting survival (1). As a single agent, rituximab was shown in a nonrandomized pivotal trial of 166 patients with relapsed low-grade lymphoma to have an ORR of 48% and a complete response (CR) of 6% (2). Lacking significant myelosuppression, investigators immediately recognized that rituximab was an ideal agent to combine with chemotherapy. Phase II studies combining chemotherapy with rituximab in relapsed and previously untreated patients with FL showed impressive ORR and CR rates of 90% to 100% and 50% to 70%, respectively (3, 4). Subsequently, two large randomized trials confirmed the benefit of combining chemotherapy with immunotherapy with CR rates of 41% and 20% compared with 10% and 17% with chemotherapy alone, significantly longer duration of response, and possibly, a survival advantage (5, 6).Radioimmunotherapy is a promising new therapy demonstrating complete and partial responses in chemotherapy and rituximab refractory patients. As early as 1996, a phase II study using single agent 131-iodine (I) tositumomab (Bexxar; GlaxoSmithKline), in previously untreated patients with FL, resul...