The safety and activity of obinutuzumab (GA101) plus chemotherapy in relapsed/refractory follicular lymphoma was explored in 56 patients. Participants received GA101 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks, 6-8 cycles) or GA101 plus fludarabine and cyclophosphamide (G-FC; every 4 weeks, 4-6 cycles). Patients were randomized to either GA101 1,600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for GA101 maintenance (3-monthly). Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68%; G-FC, 82%). Grade 3/4 IRRs were rare (7%) and restricted to first infusion. All patients received the planned GA101 dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43%) and G-FC (50%). At induction end, 96% (27/28; CR, 39% [11/28]) of patients receiving G-CHOP and 93% (26/28; CR, 50% [14/28]) receiving G-FC achieved responses. GA101 plus CHOP or FC had an acceptable safety profile, with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. GA101 plus chemotherapy resulted in 93% to 96% response rates, supporting phase 3 investigation. (Registered at www.clinicaltrials.gov: NCT00825149).