BACKGROUND: Rheumatoid arthritis (RA) patients with an inadequate response to TNF inhibitors (aTNF) may switch to an alternative aTNF or start a treatment from a different class, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. OBJECTIVE: To analyze the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. METHODS: This is a prospective cohort study of RA patients who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA). The primary outcome, longitudinal improvement in DAS28, was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. RESULTS: Of the 318 RA patients included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than alternative aTNF (p = 0.03; at 6 months, -1.34 (95% CI: -1.54; -1.15) versus -0.93 (95% CI: -1.28; -0.59) respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar between RTX and alternative aTNFs (p =0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of DMARD co-therapy. CONCLUSION: This observational study suggests that RTX is more effective than switching to an alternative aTNF in RA patients who stopped a previous aTNF treatment because of ineffectiveness.