Objectives: To assess the discontinuation of first-line biological treatment and to evaluate the reasons and predictors thereof in patients with rheumatoid arthritis (RA) from daily clinical practice. Methods: RA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) starting treatment with biologic DMARDs (bDMARDs) were included in this prospective observational study. The main outcome was the time to discontinuation (in years) due to any cause. Discontinuation was defined as a 90-day discontinuation of treatment or the occurrence of any switch to another bDMARD during follow-up. Baseline and time-varying sociodemographic and clinical characteristics were tested as possible predictors of discontinuation using multivariable Cox models. Results: Of the 1,851 RA patients included in the study, 871 (47%) discontinued their first bDMARD. The median overall persistence of the first bDMARD was 5.5 years and the leading cause of discontinuation was inefficacy [N=476 (55%)], followed by adverse events [N=262 (30%)], other causes [N=69, (8%)] and unknown causes [N=64 (7%)]. Patients with a higher HAQ score (more disability) at baseline were more likely to discontinue their first bDMARD [hazard ratio (HR):1.39 (95% CI: 1.17-1.64)], as were patients with a higher number of comorbidities [HR: 1.17 (1.05-1.29)] and patients starting treatment from 2007 onwards [HR:1.89 (1.5-2.38)]. On the contrary, receiving TNFi bDMARD [HR:0.74 (0.57-0.94)] as opposed to non-TNFi was associated with less discontinuation. Expectedly, the higher the DAS28 during follow-up the higher the likelihood to discontinue bDMARD [HR:1.08 (1.06-1.1)]. No other time-varying predictor was found. Conclusion: In the Portuguese RA population, maintenance of first-line bDMARD was shown to be relatively high. Inefficacy was the leading cause of discontinuation. Features found to predict drug discontinuation (e.g. baseline disability) may contribute to inform clinician’s decisions in clinical practice.