To evaluate risk factors for osteonecrosis in human immunodeficiency virus (HIV)-infected patients, demographic and clinical characteristics of case patients (n=17) and control patients (n=34) matched on initial clinic visit date, length of follow-up, and baseline CD4 cell count were compared. Case patients were more likely to have received corticosteroids (47.1% vs. 8.8%; matched odds ratio [OR], 13.1; 95% confidence interval [CI], 1.6-106), to have had an increase in CD4 cell count from nadir >0.050 x 10(9) cells/L (64.7% vs. 35.3%; OR, 4.9; 95% CI, 1.0-24), and to have had Pneumocystis carinii pneumonia (52.9% vs. 11.8%; OR, 7.6; 95% CI, 1.6-36). Use of protease inhibitors and history of other opportunistic infections did not significantly differ. In multivariate analysis, use of corticosteroids remained significantly associated with osteonecrosis, independently of HIV disease stage and protease inhibitor therapy. Corticosteroid use is an important risk factor for osteonecrosis, but its pathogenesis is likely multifactorial.