Tumor necrosis factor is a cytokine produced by activated macrophages that causes hemorrhagic necrosis in various tumours. In preliminary clinical trials, patients have developed various degrees of respiratory insufficiency following administration of rTNF. Twenty-seven patients were studied prospectively to evaluate the effect of administration of rTNF on pulmonary function. Sixteen of the 27 patients completed the eight-week course of daily IM injection of rTNF. Spirometric data and Dsb were measured at baseline and on days 8, 15, and 56 of treatment. Both patients with and without progressive pulmonary metastases demonstrated a comparable mean decline in Dsb (-10.7 +/- 9.6 percent [+/- SD] and 14.7 +/- 10.0 percent, respectively; p less than 0.01) not accounted for by either a decline in the hemoglobin content of the blood or a reduction in alveolar volume. Marked interindividual variability in the response of Dsb to rTNF therapy was noted. The reduction in Dsb reached a plateau by day 15. In contrast, alveolar volume and FVC remained essentially unchanged throughout the course of treatment. Measurements of Dsb performed two weeks after cessation of rTNF therapy in seven of the 27 patients showed only a modest trend toward recovery, which was not statistically significant. We conclude that the administration of rTNF for the treatment of malignant neoplasms in this dosage and schedule can cause significant pulmonary injury reflected by a reduction in Dsb which reaches a plateau by two weeks after initiation of therapy.