We evaluated the efficacy and toxicity of cyclosporine A (CsA) in combination with methotrexate (MTX) or hydroxychloroquine (HCQ) in patients with refractory rheumatoid arthritis (RA). Fourteen patients with active RA who had failed to respond adequately to injectable MTX and 14 who had failed to respond to oral HCQ had CsA added to their regimens for 6 months. Adverse effects were monitored every 2 weeks for 2 months, and monthly thereafter; outcome parameters were assessed at 0, 3, and 6 months. The starting dose of CsA was 2.5 mg/kg/day in both groups. Twenty-four patients (12 in each group) completed the 6-month study. All clinical variables (except grip strength in the HCQ + CsA group) significantly improved with both treatment regimens. Global efficacy was evaluated by means of the composite Chronic Arthritis Systemic Index. Fifteen patients (9 in the MTX + CsA and 6 in the HCQ + CsA group) could be considered responders, and 9 non-responders. The final mean daily dose of CsA was 3.3 +/- 0.8 mg/kg in the HCQ + CsA group and 3.1 +/- 0.9 mg/kg in the MTX + CsA group. Mild adverse events were more frequently observed in the MTX-CsA than in HCQ + CsA-treated patients (33 events in 11 patients as against 20 in nine). In combination with HCQ or MTX, CsA, over a 6 month period, may improve efficacy in patients with refractory RA without any significant increase in toxicity; MTX + CsA seems to be slightly more efficacious and more toxic than HCQ + CsA. Larger prospective controlled trials are necessary to define the efficacy of these combinations.