Distinguishing endocarditic from nonendocarditic septicemias is prognostically and therapeutically important. One hundred two patients with both valvular and nonvalvular sepsis were studied for the presence and quantitation of circulating immune complexes. Ninety per cent of the patients with infective endocarditis versus 50 per cent of septic patients without infective endocarditis had circulating immune complex levels (p less than 0.005). Mean circulating immune complex levels in patients with infective endocarditis were significantly higher than in those without infective endocarditis, 106 +/- 18.58 microgram/ml versus 31 +/- 7.4 microgram/ml (p less than 0.005). Only three of 52 patients without infective endocarditis had circulating immune complex levels greater than 100 microgram/ml, as opposed to 16 of 50 patients with infective endocarditis (p less than 0.005). Similarly, one of 52 patients without infective endocarditis has circulating immune complex levels greater than 200 microgram/ml, as opposed to eight of 50 patients with infective endocarditis (p less than 0.05). In 92 per cent of the patients without infective endocarditis and 76 per cent of those with infective endocarditis peak circulating immune complex levels developed within 14 days after their entry into the study, often on the initial sampling. In febrile, septicemic patients with clinical symdromes nonclassic for endocarditis, measurements of serial circulating immune complex levels may be of adjunctive diagnosis importance. If circulating immune complex levels are undetectable, endocarditis would appear less likely; alternatively, levels above 100 to 200 microgram/ml would suggest a valvular rather than nonvalvular septic focus.