Immunotherapy with interleukin-2 (IL-2) has been limited by dose-dependent systemic toxicities secondary effects inducing a "vascular leak" syndrome. The purpose of our study was directly to observe and to quantitate changes in skin capillary permeability in response to microinjection of IL-2 by measuring transcapillary diffusion of sodium fluorescein. Twelve healthy volunteers were studied. IL-2 (2.5 microliters; 45,000 i.u.) was injected into the subepidermal skin layer of the distal tibial plateau by using a new microinjection technique. At the opposite leg, an equivalent amount of the solvent was injected to serve as the intraindividual control site. Three and 24 h after injection, Na-fluorescein was given intravenously, and transcapillary diffusion of the dye was simultaneously recorded with two different video microscopes. Perivascular fluorescent light intensities (FLI) corresponding to transcapillary diffusion of the dye were measured in arbitrary units (AU) by videodensitometry around the sites of microinjection during playback of the videotapes. Mean FLI values representing microvascular permeability 10 s after dye appearance were at 3 h, 1,504 +/- 592 AU for IL-2 and 983 +/- 652 AU for the solvent; and at 24 h, 2,450 +/- 447 AU for IL-2 and 658 +/- 329 AU for the solvent. At 3 and 24 h, the mean values after IL-2 application were significantly enhanced (p < 0.05-0.005) when compared with the mean values after injection of the solvent. The results document that IL-2, as compared with the solvent, significantly increases transcapillary diffusion of Na-fluorescein, reflecting capillary permeability in human skin. The increase in capillary permeability may explain the edema-promoting effect of IL-2 after systemic application.