BACKGROUND: Rituximab is known as an efficacious drug for the treatment of Rheumatoid Arthritis (RA). The original administration schedule consisted of two infusions of 1000 mg with a 2-week interval. We aimed to explore the long-term effectiveness of rituximab in daily clinical practice in patients with RA. METHODS: Data of patients with RA treated with rituximab in a tertiary university hospital (2006-2019) were retrospectively collected from rituximab initiation until December 1st 2019 or rituximab discontinuation, whichever came first. Rituximab retreatment was based on a treat-to-target-approach guided by a 28-joint disease activity score (DAS28) ≥ 3.2, as dictated by national reimbursement criteria. Rituximab retention rate was investigated using a Kaplan-Meier survival curve. RESULTS: We collected data of 104 patients (59% female, 94% RF/ACPA-seropositive). At rituximab initiation, patients had a mean ± SD age of 58 ± 12 years and median disease duration of 12 (IQR 5-17) years. Patients were followed for a median of 40 (IQR 14-80) months and received a median of 3 (IQR 2-6) rituximab cycles. In total, 9% (9/104) patients discontinued rituximab and 14% (15/104) were treated with a reduced dose. Inherent to the retreatment strategy, disease activity fluctuated with a DAS28-increase before every new rituximab administration. Similar fluctuations were noticed for patient and physician reported outcomes. Proportion of patients continuing rituximab after three years was 94% (95% CI 89% - 99%). CONCLUSIONS: Although rituximab can be considered as an efficacious drug for RA treatment in daily practice, fluctuations in disease activity were noticed related to the retreatment approach, accompanied by impaired patient's wellbeing. TRIAL REGISTRATION: Not applicable.