Systemic administration of recombinant interleukin-2 (rIL-2) has been shown to be promising against certain metastatic cancers. However, major side effects, such as pulmonary edema, have limited its widespread use. Although this pulmonary edema has been attributed to a vascular leak syndrome, this hypothesis has not been verified in humans. The purpose of our study was to determine both the severity and mechanism of pulmonary edema in seven patients treated with rIL-2. The severity of edema was assessed by daily evaluation of chest radiographs, using a semiquantitative scale, as well as by repeated measurements of the alveolar-to-arterial oxygen gradient (A-aDO2) in each patient. To determine the mechanism of pulmonary edema, we serially measured in each patient the lung clearance of technetium 99m-diethylenetriamine pentaacetic acid (DTPA) 99mTc-DTPA), the plasma levels of Von Willebrand factor antigen, and the pulmonary capillary wedge pressure (PCWP). Our results show that there was a gradual increase in the chest radiography edema score that was paralleled by a significant increase in A-aDO2 over its baseline value. During rIL-2 treatment, 99mTc-DTPA clearance was augmented, and the plasma concentration of Von Willebrand factor antigen was elevated. PCWP climbed from 7 to 14 mm Hg and serum total protein fell from 66.1 to 42.1 gm/L. The results obtained indicate that although pulmonary edema associated with rIL-2 treatment is partially dependent on increased permeability of the lung, changes in hydrostatic and oncotic forces may be the principal determinants of edema development.