A case-control study of patients with acute leukemia was done to identify significant risk factors for invasive pulmonary aspergillosis by reviewing the medical histories of 15 cases of pathologically proven invasive pulmonary aspergillosis and 45 controls. A history of lung or sinus disease, smoking, and multiple recurrences of leukemia did not increase the risk of invasive pulmonary aspergillosis. Cases and controls received similar chemotherapeutic regimens, and exposure to aminoglycosides, carbenicillin, trimethoprim-sulfamethoxazole, or corticosteroids was not significantly associated with development of invasive pulmonary aspergillosis. Among the factors tested, only granulocytopenia was associated with development of invasive pulmonary aspergillosis. Early in the course of granulocytopenia, patients developed signs of invasive pulmonary aspergillosis at a rate of approximately 1% per day. As the duration of granulocytopenia increased, the rate increased, approximating 4.3% per day between the 24th and 36th days. Of the 13 patients remaining granulocytopenic at 28 days, 7 had developed signs of invasive pulmonary aspergillosis. For patients with acute leukemia, granulocytopenia persisting longer than three weeks is the major risk factor for developing invasive pulmonary aspergillosis.