Rheumatoid arthritis patients are at heightened risk for infections because of intrinsic disease severity with associated inflammation, comorbid illnesses, and use of glucocorticoids and various immunosuppressives. Although several studies have reported up to a twofold increase in risk of serious infections in RA patients treated with anti-tumor necrosis factor-alpha agents, results from other studies have been conflicting. Comparing results from different studies is challenging because of differences in patient populations, heterogeneous prevalence of comorbidities, and differing patterns of concomitant medication use. Based on available evidence, an excess risk for infection occurs early after initiation of tumor necrosis factor-alpha inhibitor therapy. Additionally, special circumstances such as surgical procedures may increase infection risk. The appropriate use of biologics in the perioperative setting remains empiric at best.