Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic FL. Phase II studies of chemo-free combination immunotherapy with lenalidomide and rituximab (R²) show promising activity. Methods: RELEVANCE is a global, randomized, phase III trial (NCT01650701) of R² vs R-chemo followed by rituximab in previously untreated grade 1-3a FL patients requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m² weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator’s choice of standard R-CHOP, R-bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints of CR/CRu at 120 wk and PFS (50% interim analysis by 1999 IWG) are reported here. Results: As of 31May2017, 1030 patients with high tumor burden were randomized to R² (n = 513) and R-chemo (n = 517; 72% R-CHOP, 23% R-B, 5% R-CVP); baseline characteristics were similar in both groups. At a median follow-up of 37.9 mo, superiority for R² over R-chemo was not established for both co-primary endpoints (Table). Toxicity profiles for R² vs R-chemo differed, with higher grade 3/4 lab (34% vs 50%) and febrile (2% vs 6%) neutropenia with R-chemo, and higher grade 3/4 cutaneous events (7% vs 1%) with R². SPMs were reported in 7% R² and 9% R-chemo patients and grade 5 AEs were 1% for both. 69% R² and 71% R-chemo patients completed treatment. Conclusions: In the first randomized phase III comparison of a chemo-free regimen vs standard R-chemo followed by rituximab maintenance in previously untreated FL, R² showed similar efficacy and a different safety profile to R-chemo. Clinical trial information: NCT01650701