The authors studied peripheral blood (PB) and bone marrow (BM) biopsy specimens from 12 patients treated with recombinant alpha 2 interferon (raIFN) for hairy cell leukemia (HCL), to assess changes caused by raIFN therapy. Specimens were obtained immediately before therapy and during follow-up periods for 6 months to 12 months. Before raIFN, 11 patients had hairy cells (HC) in the PB; 11 were granulocytopenic; 12, monocytopenic; and 6, thrombocytopenic. The median bone marrow hairy cell index (HCI = %HC X %BM cellularity/10,000), an indicator of HC packing in the BM, was 0.56 (range, 0.12-0.83). The myeloid:erythroid (M:E) ratio was below 1:1 in all patients. By the end of the study, HC in the PB had disappeared or decreased in numbers. Granulocytopenia, monocytopenia, and thrombocytopenia had resolved in 10 of the 11, 10 of the 12, and 5 of the 6 patients, respectively, in whom they were present before raIFN. The numbers of large granular lymphocytes (LGL) increased in 11 patients after raIFN, but often fluctuated, and in 3 patients fell to pre-raIFN values. In the BM, improvement was noted with median HCI of 0.12 (range, 0.03-0.4). In no case were HC completely absent from the BM. The BM showed increased percentages of granulocytic elements in 11 patients, of erythroid precursors in 12, and of megakaryocytes in 10. However, the M:E ratio was 1:1 or higher in only six patients at any time during the study. Marrow reticulin fibers remained increased. This study morphologically confirms the clinical improvement reported in patients with HCL who are treated with recombinant alpha 2 interferon.