Early identification of a high risk patient subgroup with infective endocarditis which develops a major complication (emboli, congestive heart failure, surgery for valve replacement, or death) during hospitalization would reduce morbidity, mortality and cost. Thus, for 74 patients with native valve infective endocarditis with documented vegetation by transthoracic two-dimensional echocardiogram, we reviewed 67 variables: history (15), physical examination (9), hematology/miscellaneous (7), chest X-ray (2), electrocardiogram (4), transthoracic two-dimensional echocardiograms (15) and hospital course (15). There were 48 men and 26 women, ages 45 +/- 19 years: 35 intravenous drug abusers and 39 non-users. There were 32 mitral, 21 tricuspid, 20 aortic, and 1 pulmonic valve vegetations; mean vegetation size was 1.4 +/- 0.9 cm2. Over the course of their hospitalization, 14 patients died (19%), 27 developed congestive heart failure (36%), 27 had systemic emboli (36%), and 22 required surgery (30%). The incidence of complications (death, heart failure or embolic events) did not differ between the drug abusers and non-users. Initial complaint of dyspnea on admission predicted the subsequent development of heart failure (P < 0.001), and a pre-admission embolus predicted a second in-hospital embolus (P < 0.001). Left atrial size, ventricular systolic or diastolic dimension did not effect prognosis. Importantly, a vegetation > 1.8 cm2 was 100% specific but only 30% sensitive for predicting the development of a complication. Vegetation mobility, shape, and number of cusps involved were not predictive. However, aortic valve vegetations had significantly more complications than those on the mitral valve (P < 0.03). By discriminant function analysis, 87% of major complications were predicted with the patient profile of having aortic valve vegetation, dyspnea on admission, prolonged preadmission fever, and no history of drug abuse; 75% of patients who developed heart failure were predicted by their having aortic valve vegetation, dyspnea, hypotension (systolic < 90 mm Hg), and no history of drug abuse; and 77% of patients requiring surgery were predicted by their having larger vegetation size, rales, and leftward shift of white blood cells. Thus, in native valve bacterial endocarditis with transthoracic echocardiographic documented vegetations, non-drug abusers with aortic vegetations, preadmission prolonged fevers, dyspnea, emboli and larger sized vegetations are at high risk for developing a major complication during their hospitalization.