We report follow-up information on 69 hairy cell leukemia (HCL) patients treated with interferon alfa-2b (IFN) as primary treatment from 1983 to 1986. Follow-up through April, 1993 shows that only 14 patients have expired. Forty-seven of the 61 patients completing the intended 12 or more months of initial IFN treatment were eventually considered IFN failures. Forty-three required re-treatment (41 received a second course of IFN and 2 received pentostatin). Four patients died without further therapy for HCL. The median time to interferon failure was 31.3 months. Fourteen patients are alive and have not required further treatment after completing their initial 12 or more months of interferon. Fifteen patients underwent a third course of interferon therapy at a median time after completion of a second course of IFN of 1.0 year. Eighteen patients were eventually treated with pentostatin and ten with 2-chlorodeoxyadenosine (2-CdA). Thirteen patients developed a second malignancy; six of these patients developed a hematologic malignancy between 44.6 months and 99.1 months after initiation of interferon therapy. We conclude that although interferon provides excellent palliation, that most patients will eventually require further treatment with interferon or chemotherapy. Future trials in HCL must be aware of the risk of second malignancies.