Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow-up (ie > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high-tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab and outcome was updated. With a median follow-up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary endpoint) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001 respectively). Considering long-term toxicity, the addition of rituximab in first line setting was confirmed as safe with regards to secondary malignancies development. Long-term follow-up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. This study was registered at ClinicalTrials.gov number NCT00136552.