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Patients injected systemically with recombinant human interleukin-2 (rhIL-2) for treatment of solid tumor develop a vascular leak syndrome (VLS), characterized mainly by pulmonary edema whose pathogenesis is unknown. We have examined the structure of pulmonary vessels in mice with severe VLS induced by systemic injections of rhIL-2 and recombinant human interferon-alpha-A/D (rhIFN-alpha), which has a synergistic effect with IL-2. The pulmonary edema was associated with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells. These changes were more severe and diffuse than those seen in mice systemically injected with rhIL-2 alone, and in beige mice (deficient in NK cells and certain enzymes of polymorphonuclear leukocytes) injected with rhIL-2 and rhIFN-alpha. The endothelial lesions were comparable to those seen when leukocytes activated by cytokines react with activated endothelial cells in vitro, or at the site of injection of cytokines in vivo. The observations are in agreement with the interpretation that the severe lesions occurring in mice systemically injected with rhIL-2 with rhIFN-alpha result from the interaction of leukocytes with the endothelium. The results confirm the validity of previous studies performed in vitro or in animals injected intradermally with cytokines and extend their significance.