High-dose recombinant leukocyte A interferon (50 X 10(6) U/m2 body surface area, intramuscularly, three times weekly) was tested in a clinical trial involving patients with advanced cutaneous T-cell lymphomas to determine its effectiveness and toxicity. All 20 patients had advanced stages of disease refractory to two or more standard therapies. Objective partial remissions lasting 3 months to more than 25 months (median, 5 months) were documented in 9 patients. The major dose-limiting toxicity was a severe influenza-like syndrome with malaise, anorexia, depression, weight loss, and decreased performance status; this effect was reversible after dose reductions in all patients and did not recur with re-escalation of doses in 10 patients. This interferon preparation is highly effective in the treatment of advanced refractory cutaneous T-cell lymphomas, and new schedules to reduce toxicity and achieve complete responses, combined treatment with chemotherapy or serotherapy, and its use in earlier stages of disease should be investigated.