Objective: To investigate the clinical effects of rituximab treatment in relation to immunological effects of rituximab on tissue-derived B lineage cells and repopulation of circulating B cells. Methods: A total of 24 patients with rheumatoid arthritis (RA) were treated with 2×1000 mg rituximab and assessed clinically at 4, 12, 18 and 24 weeks using a 44-joint Disease Activity Score (DAS44). Synovial biopsies were analysed with immunohistochemistry at baseline and 12 weeks after treatment. Peripheral blood mononuclear cells were analysed by high sensitivity flow cytometry at all timepoints. Results: In this study, a cohort of patients was dichotomised according to those who achieved a low disease activity score (DAS442.4: HiA group) at any time after rituximab treatment. At baseline, the low activity (LoA) group had significantly lower DAS44 scores (median 3.33, range 2.84 to 4.23) than the high activity (HiA) group (median 3.73, range 3.03 to 5.23; p = 0.022) and significantly less histological inflammation in synovium (median 6.7, range 1 to 15 vs 16.6, range 4 to 22; p = 0.036). DAS44 scores before and after rituximab treatment were associated with synovial infiltration of CD79a+ CD20− B cells, morphologically resembling plasma cells. Following treatment with rituximab, the LoA group had significantly reduced repopulation of circulating pre-switched IgD+ B cells (median 0.044%, range 0.002 to 0.66 vs 0.45%, range 0.07 to 9.47; p = 0.006) and post-switched CD27+ B cells (median 0.17%, range 0.04 to 0.39 vs 0.67, range 0.08 to 2.05; p = 0.005) compared to the HiA group. Conclusion: The present study demonstrated that a low disease activity state following rituximab was associated with reduced infiltration of CD79a+ CD20− plasma cells in synovium and reduced B cell repopulation.