Since April 1985, 82 patients with HCL entered a multicenter study using lymphoblastoid alpha-interferon; 51 (including 15 who failed splenectomy and 24 with substantial splenomegaly) enrolled before April 1986 are evaluated in this study. The patients were treated with 3 mega units daily subcutaneously until complete or partial response and were thereafter randomly allocated to a maintenance regime of 3 mega units/week or to observation only. Ten cases had a complete response, 18 a partial response, and 15 a minimal response. Two patients had no response, two interrupted therapy due to major toxicity (toxic hepatitis and thrombocytopenia), six died before completing 1 month of therapy of sepsis, and two died of myocardial infarction. In the two groups of splenectomized and nonsplenectomized patients the mean time to hemoglobin recovery was 8.5 and 6.5 weeks, respectively, the neutrophil count recovery was 6.5 and 9.3 weeks, and the time to platelet count recovery was 4.0 and 5.4 weeks, respectively. No significant differences in recovery time and response rate were observed between the two groups. In 31 out of 32 patients with substantial splenomegaly the spleen became either inpalpable (18) or significantly smaller (13). This study confirms the responsiveness of HCL to IFN in nonsplenectomized patients with high tumor burdens and is therefore recommended as a first-line therapy.