Abstract Purpose: To determine if platelet-activating factor (PAF) is a key mediator of lipopolysaccharide (LPS)-induced myocardial depression in guinea pigs. Methods: Hartley guinea pigs of either sex received intraperitoneal (IP) injections of either vehicle (n = 45) or one of three chemically dissimilar PAF receptor antagonists (n = 38) followed 30 to 60 minutes later by IP injections of either saline (0.8 mL, n = 33) or LPS (2 to 4 mg/ kg, n = 50). Left atria (LA) were harvested 16 hours later, suspended in Krebs-Henseleit buffer and attached to force-displacement transducers. Starling and force-frequency curves, contractile function in the potentiated and resting states, and inotropic response to either isoproterenol or phenylephrine were measured. Results: LPS caused a significant reduction in LA contractile function. Two of the three PAF receptor antagonists failed to ameliorate LPS-induced alterations in cardiac function. The third antagonist, SR27417, was approximately 50% effective in preventing LA contractile dysfunction. However, this beneficial response appeared to be caused by a primary inotropic effect of SR27417 because LA from animals treated with SR27417 and saline showed significantly higher contractile function compared with LA from animals treated with vehicle and saline. In vitro tests confirmed this. Some LA from LPS-treated animals exhibited reduced contractile responses when in the potentiated state, a sign of impaired calcium release from the sarcoplasmic reticulum (SR). The response of LA from endotoxic animals to isoproterenol was unchanged compared with controls whereas it was markedly impaired to phenylephrine. Use of SR27417 failed to improve this abnormal response. Conclusions: PAF does not appear to be a primary mediator of LIPS-induced myocardial depression in guinea pigs. LPS may impair SR calcium release thereby causing cardiac dysfunction.