Diffuse pulmonary infiltrates and acute respiratory compromise frequently occur in patients with cancer who are undergoing chemotherapy, and treatment remains controversial. We initiated a prospective randomized trial in 22 nonneutropenic patients to compare the efficacy of immediate open lung biopsy with that of empirical trimethoprim-sulfamethoxazole and erythromycin therapy with delayed open lung biopsy if no clinical improvement occurred after 4 days of therapy. Diagnoses included non-Hodgkin's lymphoma (15 patients), T-cell lymphoma (2), acute lymphoblastic leukemia (3), Hodgkin's disease (1), and breast cancer (1). The median age was 40 years, and fever (18) and tachypnea (13) were the most frequent signs. Median room air arterial oxygen tension in 18 hypoxic patients was 53 mm Hg; 19 patients had diffuse pulmonary infiltrates. Eight of the 10 patients randomized to empirical antibiotic therapy showed improvement after 4 days. The 2 patients whose condition did not improve and who underwent delayed open lung biopsy had Pneumocystis carinii pneumonia. One of them did show improvement, and the other died of respiratory failure. Time to clinical resolution in the 9 surviving patients was 14 days; 4 required prolonged ventilation (longer than 24 hours). Findings for the 12 patients randomized to immediate open lung biopsy were P. carinii pneumonia in 7 and nonspecific pneumonitis in 5; there were 3 deaths related to open lung biopsy. Time to resolution in the surviving patients was 13 days for those with P. carinii pneumonia and 5 days for those with nonspecific pneumonitis; 7 required prolonged ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)