Although the efficacy of tumor necrosis factor (TNF) antagonists for the treatment of rheumatoid arthritis (RA) has been established in randomized controlled trials (RCTs), safety concerns have emerged, particularly with regard to risk of infection, malignancy, and cardiovascular (CV) outcomes. Because of the shorter duration and limited number of patients enrolled in RCTs, evidence regarding the risk of rare adverse outcomes is frequently inconclusive. Longterm observational studies, as well as RCT meta-analyses, provide additional safety data. This review discusses the emerging evidence from observational registries on the risk of infection, malignancy, and CV outcomes associated with TNF antagonists.