We previously observed degranulated mast cells (MC) in association with perivascular brain edema formation during focal cerebral ischemia. Brain MC are typically located perivascularly and contain potent fast-acting vasoactive and proteolytic substances. We examined in a rat model of transient middle cerebral artery occlusion (MCAO) whether, in the early phase of ischemia, MC regulate microcirculation, the blood–brain barrier (BBB) permeability, and edema formation. First, animals received MC inhibitor (cromoglycate), MC-degranulating drug (compound 48/80), or saline. Thereafter, we performed transient MCAO in gene-manipulated MC-deficient rats and their wild-type (WT) littermates, calculating brain swelling, visualizing BBB leakage by intravenously administered Evans blue albumin, and determining neutrophil infiltration with light microscopy. Cerebral blood flow, monitored by laser-Doppler flowmetry in separate experiments, was similar among pharmacological treatments. Ischemic swelling resulted in increased hemispheric volume of 13.4% ± 1.0% in controls, 8.1% ± 0.4% (39% reduction) after cromoglycate, and 25.2% ± 2.0% (89% increase) after compound 48/80 ( P < 0.05). Early ischemic BBB leakage was reduced by 51% after cromoglycate, and 50% enhanced by compound 48/80 ( P < 0.05). The cromoglycate group showed 37% less postischemic neutrophil infiltration than did controls ( P < 0.05). Furthermore, MC-deficient rats responded to focal ischemia with 58% less brain swelling (6.7% ± 1.2%) than did their WT littermates (15.8% ± 1.4%, P < 0.05). Blood-brain barrier damage was 47% lower in MC-deficient rats than in the WT ( P < 0.05). Neutrophil infiltration after MCAO was decreased 47% in MC-deficient rats in comparison to WT ( P < 0.05). Pharmacological MC inhibition thus appears to deserve further investigation regarding reduction of brain swelling and inflammation early after stroke.