Iliac crest trephine biopsy specimens from 16 patients treated with recombinant alpha 2-interferon (alpha-IFN) for hairy cell leukemia (HCL) were examined for reticulin and collagen content. These data were compared with the hairy cell index (HCl), the proportion of hairy cells to the overall cellularity of the bone marrow. Specimens were studied immediately before alpha-IFN therapy, at 6-month intervals during, and in six patients 6 months after cessation of therapy. All patients presented with increased bone marrow fibrosis ranging from focally increased reticulin to a diffuse increase in both reticulin and collagen content. This fibrosis was observed to decrease during alpha- IFN therapy inasmuch as the hairy cell population was diminished in the bone marrow in 13 patients. Regression analysis of HCl v bone marrow fibrosis showed a positive correlation (r = .73, P less than .02). Six patients demonstrated a reduction in bone marrow reticulin and collagen to normal levels during alpha-IFN therapy. Two of six patients demonstrated increased bone marrow fibrosis and HCl 6 months after cessation of alpha-IFN therapy. Three of 16 patients exhibited no decrease in bone marrow reticulin content during therapy despite a decreased bone marrow hairy cell population.