We evaluated the safety, tolerability, pharmacodynamics, and activity of B‐cell depletion with rituximab in patients with relapsing‐remitting multiple sclerosis, receiving two courses of rituximab 6 months apart, and followed for a total of 72 weeks. No serious adverse events were noted; events were limited to mild‐to‐moderate infusion‐associated events, which tended to decrease with subsequent infusions. Infections were also mild or moderate, and none led to withdrawal. Fewer new gadolinium‐enhancing or T2 lesions were seen starting from week 4 and through week 72. An apparent reduction in relapses was also observed over the 72 weeks compared with the year before therapy. Ann Neurol 2008