Histochemical and functional properties of mast cells (MC) in Brown Norway rats recovering from chronic treatment with the MC secretagogue compound 48/ 80 were examined. In the skin, treatment for 5 days with compound 48/80 resulted in a marked decrease in MC subpopulations defined by differential alcian blue/safranin staining. Both safranin-positive connective tissue MC and alcian blue staining MC were reduced in number. This was accompanied by significant decreases in skin histamine and rat MC serine protease I contents and a loss of specific IgE-mediated passive cutaneous anaphylaxis (PCA) activity. The PCA reaction did not return to normal before 2 months after stopping treatment and only when the numbers of safranin-positive connective tissue MC and skin histamine content reached pretreatment levels. The subepidermal alcian blue staining MC not eliminated by the compound 48/80 treatment were formalin resistant (unlike alcian blue staining mucosal MC of the intestine) and apparently played no role in the PCA response. MC numbers, histamine levels, and rat MC serine protease 1 content of the tongue were similarly decreased by compound 48/80. In contrast, mucosal MC of the gut were unaffected by the secretagogue treatment.