The microvascular response to two polycationic proteins, poly-L-lysine (mol wt 104,000) and leukocyte elastase, was studied in the hamster cheek pouch microcirculation model. A 2-min topical application of polylysine (100 micrograms/ml) induced vigorous macromolecular leakage from venules only that declined within 30 min. A second application induced significantly less leakage. The leakage was inhibited by admixing polylysine with dextran sulfate prior to application or by giving hamsters an intravenous injection of dextran sulfate. The histamine antagonist pyrilamine did not interfere with the leakage, and only a few degranulated mast cells were found after polylysine application. No intravascular adhesion of leukocytes could be detected. Elastase (100 micrograms/ml) was deposited adjacent to venules with micropipets. The resulting leakage response was not inhibited by L658,758, an inhibitor of elastase enzymatic activity, but by dextran sulfate. These results may prove significant in light of the numerous polycationic proteins present within neutrophil granules.