Objective: To study the effects in systemic lupus erythaematosus (SLE) of B cell directed therapy with rituximab, a chimeric monoclonal antibody directed at CD20+ B cells, without concomitant immunosuppressive therapy in mild to moderate SLE. Methods: Patients (n = 24) with active SLE and failure of ≥1 immunosuppressive were recruited from three university centres into this phase I/II prospective open-label study. Patients were followed for 1 year to assess safety, efficacy and biological effects. Results: In total, 18 of the patients scheduled to receive the full lymphoma dose of rituximab were evaluable for B cell levels in peripheral blood. Of these, 17 had effective CD19+ B cell depletion (<5 cells/μl). However, six of the depleted patients showed B cell return before 24 weeks. A total of 70% of patients improved by week 55, as defined by an SLE Disease Activity Index (SLEDAI) score improvement of ≥2 units from baseline. The degree of CD19+ B cell depletion was correlated with SLEDAI improvement at week 15 (r = 0.84). In general, rituximab infusions were well tolerated. Approximately a third of the patients developed human anti-chimeric antibody (HACA) titres, which correlated with poor B cell depletion. Most patients (9 of 14) did not respond to immunisations with Pneumovax and tetanus toxoid. Conclusions: Rituximab is a promising new therapy for SLE. The variability of responses in patients with SLE may be related to HACA formation. The failure to respond to immunisations is surprising, in view of the apparently low risk of infections. Better biological markers are necessary to follow these patients during treatment.