Objective: Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after hemorrhagic shock and resuscitation (HS/R) with administration of the MC stabilizers to prevent MC degranulation. Methods: Anesthetized male Sprague-Dawley rats were randomized to sham control or HS/R groups, and underwent 60 minutes of HS followed by 2 hours of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline, 15 minutes prior to shock. Hearts were excised following HS or 2 hours of reperfusion and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum -hexosaminidase. Hearts were excised at 0 minutes (prior to HS) and following 60 minutes of HS (prior to resuscitation) for histological evaluation of MC density and degranulation. Results: In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure (P<0.05), contractility (P<0.05), and relaxation (P<0.05), compared to HS controls. Serum -hexosaminidase increased during HS and resuscitation and was inhibited by MC stabilization (P<0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. Conclusion: Inhibition of MC degranulation can significantly improve cardiac function following HS/R.