Aim. To evaluate the impact of anti-B-cell therapy on the clinical and immunological parameters of systemic lupus erythematosus (SLE) activity, on the time course of changes in these parameters during long-term follow-up, and on the tolerability of repeated rituximab (RTM) therapy cycles. Subjects and methods. RTM was given to 97 patients with high activity of SLE refractory to treatment with glucocorticosteroids (GCS) and cytostatics. The follow-up lasted 18 (12-36) months. The most common clinical manifestations of SLE were lupus nephritis (LN) (62%) and skin (33%) and nervous system (22.7%) involvements. Clinical SLE activity was assessed applying the SLE disease activity index 2000 (SLEDAI2K); therapeutic effectiveness was evaluated using indicators, such as partial response (PR), complete response (CR) and exacerbation. The exacerbation was classified as moderate and severe using the Selena-Sledai Flare index (SFI). Results. Depletion was identified in 78% of the patients with SLE immediately after RTM therapy. During 3.5 years of follow-up, the effect of RTM was seen in 82% of the patients after repeated RMT therapy cycles (CR 56% and PR 28%). Exacerbations were observed in a total of 24 (24.7%) patients; the exacerbation lasted 12 (12-24) months after RTM therapy: of them 17.5% with LN and 7.2% with extrahepatic manifestations of SLE (exacerbations occurred 12 (12-24) and 18 (6-48) months after RMT therapy). In 24 exacerbated patients, B cells recovered at 6 (3-12) months. A year after RMT therapy, a group of 35 patients who were observed to have complete B cell depletion achieved CR statistically significantly more frequently than a group of 20 patients who had B-cell recovery (65.7 and 30% respectively, p=0.03). CR was observed significantly more often in patients after repeated RTM therapy cycles than those who had received only one RTM therapy cycle (p=0.02). The long-term follow-up showed a reduction in SLEDAI2K, normalization of laboratory values, and a decrease in the daily dose of GCS. Most patients tolerated well both the first and repeated RTM therapy cycles. Conclusion. According to the results of the long-term follow-up, RTM therapy is a highly effective treatment option for SLE patients in whom the previous standard therapy with GCS and cytostatics was previously ineffective. The 3.5-year follow-up showed a good tolerability of RTM and revealed no increase in the risk of infectious complications or adverse reactions.