We reviewed the clinical records of 6 patients with osteonecrosis and human immunodeficiency virus (HIV) infection. We conducted a literature search for the putative mechanism by which this association may occur. None of these 6 patients had other known conditions associated with a predisposition to osteonecrosis. Avascular necrosis (AVN) frequently occurred in multiple sites and early in the course of HIV infection. We suggest that HIV infection is a systemic disorder that may predispose to osteonecrosis of bone. The most likely mechanism involves thrombosis, which may be mediated by anticardiolipin antibodies and/or acquired deficiency of protein S. In patients with idiopathic osteonecrosis that involves multiple sites we recommend careful evaluation for HIV risk factors.