Data collected from a prospective multicenter study of endocarditis caused by S. aureus were analyzed to contrast the clinical presentation of the disease between a group of 46 intravenous drug addicts and a group of 35 nonaddicts. Two-thirds of the patients in each group were men. The duration of illness before diagnosis was similar (mean, 9.3 days). Intravenous-drug addicts were younger and had less underlying disease (30% versus 80%) than the non-addicts. When first seen, the drug addicts had signs and symptoms of sepsis and pulmonary embolism, but only 40% had pathologic murmurs. Seventy-six percent had evidence of tricuspid valve infection only. Congestive heart failure and neurologic manifestations were uncommon in addicts. Nonaddicts had infection involving predominantly the left side of the heart (14 mitral valves, 8 aortic valves, 4 both aortic and mitral valves) and 80% had underlying medical diseases. Only half of these patients had pathologic murmurs when first examined, but another 30% developed them later. Congestive heart failure, involvement of the central nervous system, and peripheral embolic or septic complications each occurred in over half of the nonaddicts. Eighty percent of these patients had peripheral stigmas of endocarditis. One intravenous drug addict (2%) and seven nonaddicts (20%) died. Six patients required cardiac valve replacement either during or after a course of antibiotics. Outcome was not related to the titer of peak serum bactericidal tests. Endocarditis caused by S. aureus presents as two distinct clinical syndromes depending on the patient population (intravenous drug user or nonaddict) and the location of infection (right-sided or left-sided). The disease is distinguished from endocarditis due to other causes by its acute onset and its fulminant course manifested by a multitude of septic and embolic complications and its ability to cause heart failure. Medical management alone is often successful but in certain subsets of patients, notably those with infection of aortic or multiple valves, early operation may be necessary.