The long-term outcome of patients with hairy cell leukemia resistant to interferon-alpha (IFN-alpha) following treatment with deoxycoformycin (DCF) was examined, and the kinetics of recovery of lymphocyte subsets and factors influencing the rate of recovery investigated. Between May 1986 and May 1989, 15 patients with histologically confirmed hairy cell leukemia resistant to IFN-alpha received DCF 4 mg/m2 every 2 weeks with 12 cycles planned. All 15 patients were evaluable for response and have been followed for a median of 88 months (range, 72 to 106 months) from the start of therapy. Fourteen patients responded to DCF, all attaining complete remission (CR) (response rate 93%; 95% confidence interval, 69% to 100%). Seven patients have developed recurrent disease after 45 to 74 months. Using the method of Kaplan and Meier, the median remission duration is 74 months and, at 8 years, 46% (95% confidence interval, 33% to 59%) of patients are projected to be in ongoing CR. The seven relapsing patients have responded to treatment with 2-chlorodeoxyadenosine (2-CdA) and all 15 patients remain alive. After DCF, nadir CD4+ and CD8+ lymphocyte counts were significantly lower than prior to therapy (P < 0.0001 and P = 0.05, respectively), but returned to baseline levels during follow-up. Median times to attainment of the lower limit of the normal range of CD4+ and CD8+ lymphocytes were 54 and 36 months, respectively. Those patients who had previously undergone splenectomy (n=7) had higher baseline CD4+ (P= 0.073) and CD8+ (P= 0.043) lymphocyte counts and more rapid recovery of both CD4+ (P= 0.027) and CD8+ lymphocyte counts (P = 0.016) than non-splenectomized patients. One elderly patient (age, 78 years) was diagnosed with subsequent malignancy. No late opportunistic infections were observed. Resistance to IFN-alpha does not impair subsequent responsiveness of patients with hairy cell leukemia to treatment with DCF. Responses are durable and without evidence of long-term sequelae. CD4+ and CD8+ lymphocyte subsets recover slowly without clinical manifestations of immunodeficiency. Splenectomized patients appear to have higher baseline lymphocyte counts and more rapid lymphocyte recovery following treatment with DCF.