Introduction: This study examined the effects of oral antibiotics to selectively decontaminate the digestive tract (SDD) on postburn myocardial signaling, inflammation and function. We hypothesized that antibiotic therapy to eliminate pathogens from the GI tract would reduce myocardial inflammatory responses and improve postburn myocardial performance. Methods: Sprague Dawley rats received polymyxin E, 15 mg; tobramycin, 6 mg; 5-flucytosin, 100 mg by oral gavage twice daily for 3 days pre-burn and 24 hrs postburn. Experimental groups included 1) sham burn given vehicle (3 ml water), 2) sham plus SDD, 3) burn over 40% TBSA plus SDD, and 4) burn, 40% TBSA given vehicle. All burns received lactated Ringer's, 4 mg/kg/% burn; myocardial signaling (PKC/p38 MAPK/NF-B) was studied 2, 4, and 24 hrs postburn; cytokine secretion (systemic and myocyte secreted cytokines, ELISA) and cardiac function were examined 24 hrs postburn. Results: Vehicle treated burn injury increased myocardial PKC/p38 MAPK expression, promoted NF-B nuclear translocation, promoted TNF-, IL-1, IL-6, and IL-10 secretion and impaired myocardial function. SDD attenuated burn-related pro-inflammatory myocardial signaling, cytokine secretion, and myocardial contractile defects. Conclusions: Our data suggest that burn-related loss of GI barrier function and translocation of microbial products serve as upstream mediators of postburn myocardial inflammatory signaling and dysfunction.