Isolated coronary ostial stenosis is a rare condition of unknown etiology previously reported in only 22 patients. Of 2,105 consecutive patients with angiographically defined coronary disease, 27 (1.3%) had 50% or greater stenosis of one or both coronary ostia. Serious complications occurred during angiography in three patients (11%) with one death. Coronary bypass surgery was performed in 25 patients with 1 early death (4.0%) and 1 late death (mean follow-up 28 months). Twenty-two patients (Group 1) had associated multivessel coronary disease, of whom 18 (82%) presented with stable angina of variable duration (43 +/- 53 months) and 10 (46%) were in the New York Heart Association functional class II. The prevalence of risk factors was high, especially among the eight women (3.0 +/- 0.8 per patient), seven of whom had hyperlipidemia. Five patients (Group 2) representing 0.2% of the total had isolated coronary ostial stenosis. All were women (age 41 +/- 6 years). In contrast to patients in Group 1, this group presented with a short history (2.0 +/- 1.7 months) of severe angina and had a low incidence of risk factors (0.8 +/- 0.6 per patient). Histopathologic study in one case showed typical atheroma. Isolated coronary ostial stenosis is a rare lesion occurring predominantly in young or middle-aged women. The clinical and angiographic profile appears unique and, despite the histopathologic findings, suggests a natural history distinct from that usually seen in atherosclerotic coronary disease.