The objective of this study was to characterize the role of mast cells in the development of vasculitis and joint swelling in adjuvant-immunized rats. Leukocyte trafficking within mesenteric venules (rolling and adhesion) and mast cell activation (ruthenium red uptake) were examined in vivo. Elevated leukocyte trafficking was observed by 4 days after immunization, whereas joint swelling developed between days 10 and 12. Perivascular mast cells took up ruthenium red and appeared activated by electron microscopy at 4 but not 12 days after immunization. Treatment with the mast cell stabilizer cromolyn on days 1 to 4 after immunization blocked ruthenium red uptake at day 4 and reduced leukocyte rolling and adhesion by approximately 50%. This treatment also reduced rolling, adhesion, and joint swelling at day 12 by approximately 50%. Cromolyn treatment over days 9 to 12 reduced joint swelling but increased leukocyte emigration into the mesentery. Peritoneal mast cells isolated 4 days after immunization elicited significant neutrophil chemotaxis in vitro, whereas day 12 mast cells did not. Mast cell activation and vasculitis were absent in adjuvant-resistant Fisher/344 rats. These data suggest that mast cells play an early role in the initiation of vasculitis and may function by day 12 to limit infiltration of leukocytes from the vasculature. In the joint, however, mast cells appear to contribute to inflammation at early as well as later time points.