The effects of Cyclosporin A (CyA) on rat mucosal mast cells (MMC) have been investigated by cell counts in the jejunal mucosa and assays of the MMC-specific granule protease RMCPII in tissues and serum. CyA was administered by subcutaneous injection; for the majority of experiments the rats received 50 mg/kg daily for 3 days as a loading dose, then 50 mg/kg on alternate days. Treatment with this drug has two actions on MMC, a gradual reduction in the number of MMC and in the tissue content of RMCPII in the jejunum; and a rapid fall in the serum concentration of RMCPII, detectable 3 h after i.v. administration of CyA, 50 mg/kg. These phenomena were demonstrated in normal rats and in animals with an expanded jejunal MMC population due to graft vs host reaction or recent helminth infection. The functional relevance of the MMC depletion was demonstrated in immune rats given CyA for 3 days prior to induction of systemic anaphylaxis; intestinal permeability to i.v. Evan's blue was significantly reduced by CyA treatment. We suggest that CyA depletes intestinal MMC by suppression of T-cell-mediated regulatory stimuli to proliferation of mast cell precursors and/or their migration. The effects of the drug on serum RMCPII, evident before there were changes in the number of intestinal MMC, indicate that it also suppresses the secretion of granule mediators by MMC, probably indirectly via effects on mucosal T cells.