Ocrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy. Forty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m2 (n = 15); cohort B, 375 mg/m2 (n = 16); cohort C, first dose 375 mg/m2, seven subsequent doses of 750 mg/m2 (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics. The median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1–6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcγ receptor IIIa (FcγRIIIa). With follow-up of ∼28 months, the median progression-free survival was 11.4 months. Ocrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.