Of 14 patients with hairy cell leukemia (HCL), four developed opportunistic granulomatous infections: blastomycosis, coccidioidomycosis and two Mycobacterium kansasii. The former two pathogens have not been reported with HCL, while M. kansasii infections appear to be common. While most reviews stress susceptibility to pyogenic bacteria and the predisposing role of iatrogenic factors, three of our patients were infected prior to any therapy. Thus, disease-related factors predispose to these granulomatous infections. Granulocytopenia and monocytopenia were present; the latter was not often corrected by splenectomy. There was impaired granuloma formation, with all infectious lesions appearing histologically as focal microabscesses containing few macrophages. Awareness of the frequency of opportunistic intracellular infections with early consideration of invasive diagnostic procedures to establish specific etiologic diagnosis may greatly prolong survival for many HCL patients.