B cell targeted therapy using rituximab, a genetically engineered chimeric mouse/human monoclonal antibody, is recommended for patients with active rheumatoid arthritis who have failed to respond to both conventional disease-modifying drugs and TNF inhibitors. The value of ritixumab in patients with earlier disease, who have only failed methotrexate, was evaluated in a large multicentre randomised, placebo-controlled trial. The Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE) trial enrolled 511 patients with active rheumatoid arthritis. They received one of two doses of rituximab (500 mg × 2 or 1000 mg × 2) or placebo in addition to methotrexate therapy. By 6 months significantly more patients receiving active treatment with rituximab achieved American College of Rheumatology 20 and 50% responses and had low disease activity or remission. These benefits extended to 12 months. There was not an excess of adverse reactions with rituximab. There was some evidence, albeit incomplete, that patients who were seronegative for rheumatoid factor were less likely to respond to rituximab. There is some evidence rituximab might be suitable as first choice biologic treatment, although head-to-head trials are needed against TNF inhibitors before such an approach can be justified. Its value is likely to be restricted to seropositive patients.