OBJECTIVE To prospectively determine the efficacy and safety of etanercept in combination with sulfasalazine (SSZ), hydroxychloroquine (HCQ), and gold in the treatment of rheumatoid arthritis (RA). METHODS A prospective open-label study enrolled 119 patients with RA who had active disease despite stable therapy with SSZ (n = 50), HCQ (n = 50), or intramuscular gold (n = 19). Primary efficacy endpoints consisted of American College of Rheumatology responses at 24 and 48 weeks. Safety was established at regularly scheduled visits. RESULTS Patients in each etanercept combination showed significant improvement at both 24 and 48 weeks. Toxicity withdrawals by 48 weeks included gold (n = 1): proteinuria; HCQ (n = 5): septic wrist and bilateral pneumonia, rash, optic neuritis, breast cancer, squamous cancer of the tongue; and SSZ (n = 5): otitis media, elevated liver function indicators, pericarditis, rash, and gastroenteritis. The most common adverse events not requiring discontinuation from the study were injection site reactions (43% of patients) and upper respiratory type infections (34%). CONCLUSIONS This study is the first to prospectively evaluate the safety of etanercept in combination with SSZ, HCQ, and gold in patients with RA. Etanercept in combination with SSZ, HCQ, or gold was efficacious and well tolerated, with a discontinuation rate of 9% (11/119) for adverse events at 48 weeks.