The monoclonal anti-CD20 antibody rituximab has been shown to induce a high response rate in follicular lymphoma patients and to improve the outcome when associated with CVP or CHOP in newly diagnosed patients. Rituximab synergy with αIFN has also been established in experimental and clinical studies. In order to investigate the benefit of rituximab when added to the classical association of αIFN with CHVP (cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, etoposide 100 mg/m2 on day 1 and prednisone 40 mg/m2 day 1–5), the intergroup GELA-GOELAMS FL-2000 trial was initiated. Inclusion criteria consisted in untreated histologically proven stage II-IV follicular lymphoma (any grade) patients (18–75 years) with a high tumor burden consisting in the presence of at least one of the following criteria: B symptoms presence; ECOG PS≥1; LDH>normal value; β2-microglobulin≥3 mg/L; largest tumor≥7cm; three distinct nodes≥3cm; serous effusion, compression or symptomatic splenomegaly). Treatment in arm A consisted in CHVP (6 monthly courses + 6 courses every 2 months) associated with αIFN-2a (4.5 MU [reduced at 3 MU > 70 years] 3 times a week) for 18 months and in arm B in 6 monthly courses of CHVP associated with 18 months of αIFN-2a combined with 6 infusions of 375 mg/m2 rituximab (Day 1 and 8 course 3 & 4 ; day 1 courses 5 & 6). Patients were evaluated for response at 6 months and 18 months and followed every 3 months. From 05/2000 until 05/2002, 359 eligible patients were included (Arm A 175 pts and Arm B 184 pts) with the following characteristics: M/F =1; median age =60 years [25–75]; ECOG>1 =8%; B symptoms =27%; AA stage>II =87%; bone marrow involvement =58%; β2−m≥3mg/L =31%; LDH>N =37%; Hb≤12g/dL =18%; the FLIPI score was ≥3 in 56% of patients. This first analysis of all patients demonstrated a significant improvement of response to therapy in arm B as compared to arm A, both at 6 months [CR+CRru 49% vs. 76%; PR 36% vs. 18%; stable, progression or death 15% vs. 6%; respectively (P<.0001)] and at 18 months [CR+CRu 79% vs. 63%; PR 5% vs. 10%; stable, progression or death 17% vs. 27%; respectively (P=.004)]. With a median follow-up of 30 months, the median EFS was not reached in both arms and 104 patients presented an event. In the control arm, estimated 2.5 years EFS is of 62% versus 78% in arm B (P=.003). In conclusion, this first analysis indicate that 1) the control arm reproduces earlier results with the same regimen 2) rituximab associated with α-IFN+CHVP induces a higher response rate in high tumor burden FL patients; 3) rituximab addition to αIFN+CHVP allows to reduce the number of CHVP chemotherapy cycles and 4) this rituximab association with αIFN+CHVP results in a marked improvement of event-free survival comparing favorably to the control arm or to other rituximab+chemotherapy combinations.