Objectives: To assess adverse events (AE) associated with first-line therapies for rheumatoid arthritis (RA) in a real-world setting. Material and Methods: Retrospective multicenter cohort study of patients fulfilling classification criteria for RA and followed up in 66 rheumatology centers from the Rheumatic Diseases Portuguese Registry (Reuma.pt). All AE reports associated with first-line disease-modifying antirheumatic drugs (DMARDs) up to November 2024 were included. Demographic and clinical data were analyzed, and AE characteristics were investigated. Categorical and continuous variables were compared using chi-square tests and Mann–Whitney U tests, respectively. Statistical significance was defined as p < .05. Results: Among 1 880 AE entries, 377 (20.1%) were attributed to first-line DMARDs, most commonly methotrexate (62.9%) although no information on drug dosage was available. The median age at AE occurrence was 58.6 years (IQR: 19.32), and 82% were female. A causality assessment was available in 317 reports, with 40.3% deemed “probable,” 28.1% “possible,” and 10.6% “definitive.” Severe AE were reported in 13.2% of cases, with pulmonary involvement being the most common (20.8%).Overall, 46.7% of patients discontinued treatment for any reason. Male sex was significantly associated with severe AE (OR = 2.31; 95% CI: 1.17–4.55; p = .014), and older patients were more likely to experience severe AE (median age 65.7 vs. 57.9 years; p < .001). The most affected body organ systems were gastrointestinal (9.3%), skin (8.2%), and hematological (8.2%). The median time to AE onset from treatment initiation was 1.27 years (IQR: 2.63), and from disease onset was 8.56 years (IQR: 11.76). Conclusions: AE related to first-line RA therapies can lead to significant clinical consequences, including treatment discontinuation. Male sex and advanced age were associated with increased AE severity. The most affected systems appear consistent with known drug safety profiles, particularly that of methotrexate; however, the absence of information regarding drug dosage precludes more detailed conclusions. These findings emphasize the need for individualized monitoring strategies and improved pharmacovigilance to optimize long-term treatment safety and adherence in RA management.