We report that there is an unexpectedly high incidence of second neoplasms in patients after treatment of hairy cell leukemia (HCL) with interferon alpha 2b (IFN). In a cohort of 69 patients with HCL entered in a protocol using IFN as the primary treatment, and followed thereafter for a median of 91 months (range, 0.2 to 109 months), 13 patients (19%) developed a second neoplasm. Six neoplasms were of hematopoietic origin, whereas the remaining seven were adenocarcinomas. The expected number of second tumors in this cohort is three (based on calculations from the National Cancer Institute's SEER data), so the excess frequency (observed:expected) is 4.33. However, the excess frequency is even greater for the hematopoietic neoplasms; the expected frequency is 0.15, whereas six hematopoietic tumors occurred, for an observed:expected ratio of 40. In general, the second neoplasms have behaved aggressively, and the median survival after diagnosis of the second neoplasm was only 8.8 months. Although we cannot entirely exclude the possibility that IFN therapy has some direct oncogenic effect, we suspect that increased frequency of second tumors is related to prolonged survival of patients who are immunocompromised because of HCL and thus prone to develop second tumors. If so, the frequency of second neoplasms in patients with HCL may be even greater in the future with continued improvements in therapy.