The presence of simultaneous left- and right-sided endocarditis affecting the cardiac structures is rare and information regarding clinical presentation, pathophysiologic mechanisms, and prognosis is limited. We report the case of a young woman who presented to our institution with severe staphylococcal peritonitis and generalized sepsis who had tricuspid valve and left ventricular (LV) mural endocarditis. Significant transpulmonary shunting was demonstrated using transesophageal imaging and saline contrast injection. In this case transesophageal echocardiography (TEE) provided enhanced imaging of an unusual form of right- and left-sided endocarditis. More importantly, the use of TEE and saline contrast injection suggested an interesting hypothesis that might ultimately contribute to an improved understanding of pathophysiologic mechanisms in infective endocarditis and severe sepsis.