2-Chlorodeoxyadenosine (2-CdA) has recently established itself as an extremely effective therapy for patients with hairy cell leukemia. To date, the issue of how to treat patients relapsing after 2-CdA has not been adequately addressed. In our initial study, 41 of 46 patients achieved an objective response (complete or partial remission). The only persistent toxicity associated with this agent appears to be significant suppression of CD4+ lymphocyte counts, albeit without evidence of clinical sequelae at a median follow-up of 30 months (range, 7-43). Eight patients have developed recurrent disease 3-23 months (median, 16 months) after 2-CdA. Because of progressive cytopenias, three of these patients were treated with interferon-alpha (IFN-alpha) (3 x 10(6) units subcutaneously three times per week), commencing 2, 9 and 16 months after the documentation of relapse. All three patients have shown an objective response with reduction of marrow hairy cells and amelioration of neutropenia and thrombocytopenia (two patients, complete remission; one patient, partial remission). Responses were maintained while on IFN-alpha, but two patients relapsed shortly (3 and 4 months, respectively) after discontinuation of IFN. There was no significant toxicity. Prior to commencing IFN-alpha, 22-36 months after 2-CdA, these patients' absolute CD4+ counts were suppressed (mean 211/microliters, s.d. +/- 85/microliters), but have not significantly changed after 10, 11 and 18 months of IFN-alpha therapy (mean 225/microliters, s.d. +/- 93/microliters). These results suggest that in hairy cell leukemia patients relapsing after 2-CdA, IFN-alpha may be a reasonable therapeutic option, especially if persistent CD4+ lymphocytopenia is present.