The role of mast cells in the pathogenesis of endoneurial edema was investigated by injecting histaminergic substances into peripheral nerves and measuring endoneurial fluid pressure (EFP). Intraneural injection of Compound 48/80 into rat sciatic nerves was followed by a rise in EFP to approximately 4 times the normal level. A significant, although smaller increase in pressure took place after histamine injection, but there was no increase in EFP following either serotonin-, heparin-, or sham-injected control nerves. In each experimental animal, the contralateral sciatic nerve was injected with physiologic saline, corrected for pH and osmolarity, and employed as a control. Edema was visualized by light microscopy and quantified by morphometric analysis of nerve swelling; mast cell degranulation was illustrated by electron microscopy. Each nerve was embedded in araldite and cut in serial sections along its axis to determine the extent of edema. Increased transfascicular areas was documented in conjunction with elevated EFP during the first 2.5 hours after nerve injection. Electron microscopy confirmed that mast cell degranulation had occurred, and free granules were present in the endoneurial space. Altered vascular permeability was apparent with diapedesis of polymorphonuclear cells through vessel walls and accumulation of these cells in the endoneurial space. Our findings suggest that mast cell degranulation, when it occurs in peripheral nerve, may contribute to edema and increased EFP.