We studied the comparative safety of first-line conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) as prescribed for the treatment of rheumatoid arthritis (RA). Drugs of interest were informed by a parallel drug utilisation study, and included methotrexate, hycroxychloroquine, sulfasalazine, and leflunomide. Study outcomes included cardiovascular disease (myocardial infarction, stroke), infection/s (any, serious, opportunistic), cancer (any, lung, colo-rectal, leukemia, lymphoma) and leukopenia/pancytopenia. Routine (real world) electronic medical records and/or claims data from Germany, Spain, Belgium, France, Netherlands, United Kingdom, Estonia, Japan, and the United States of America were analysed. All subjects aged 18+, with 1+ year run-in, a diagnosis of RA, and a first-line csDMARD were included at therapy initiation. Propensity score stratification was used to minimise confounding by indication, and negative control outcomes analyses to identify residual (unobserved) confounding.