Abstract Objectives The effectiveness of TNF inhibitors in RA has been shown to be affected by obesity. No such effect has been found for abatacept and rituximab, while for tocilizumab results are ambiguous. Additionally, it remains unresolved whether sex is an effect modifier for obesity. We investigated the impact of obesity on the drug effectiveness of conventional synthetic or biologic DMARDs, taking into account potential sex-specific differences. Methods Data from 10 593 RA patients included in the German observational cohort study Rheumatoid Arthritis: oBservation of BIologic Therapy (RABBIT) since 2009 were analysed. Patients had to have a BMI ≥18.5 kg/m2, at least one follow-up and 6 months of observation time. The influence of obesity on drug effectiveness was investigated by regression analysis, adjusting for potential confounders. Results Obesity had a negative impact on improvement in the DAS with 28 joints using ESR as an inflammation marker of –0.15 (95% CI: –0.26; –0.04) units for women receiving conventional synthetic DMARDs, –0.22 (95% CI: –0.31; –0.12) units for women receiving TNF inhibitors, –0.22 (95% CI: –0.42; –0.03) units for women receiving tocilizumab and –0.41 (95% CI: –0.74; –0.07) units for men receiving tocilizumab. Overall, no negative obesity effects on the effectiveness of rituximab and abatacept were found. Conclusion Obesity has a negative impact on the effectiveness of cytokine-targeted but not cell-targeted therapies in daily practice, affecting more outcomes and therapies in women than in men. Overall, no effects of obesity on treatment effectiveness were found for rituximab and abatacept.