BACKGROUND: Hepatoportal sclerosis (HPS) is a cause of noncirrhotic portal hypertension, with patients typically presenting with variceal bleeding. It is idiopathic in nature but is felt to be due to an abnormality of the intrahepatic vasculature. HPS is characterized by varying degrees of portal fibrosis, sclerosis of portal vein branches and dilatation of sinusoidal spaces. Nodular regenerative hyperplasia (NRH), another cause of noncirrhotic portal hypertension, has also been recently described in HIV patients initially diagnosed as having cryptogenic liver disease. METHODS/RESULTS: We describe four cases of HIV+ patients presenting with noncirrhotic portal hypertension; liver biopsies were reviewed by an experienced liver pathologist and found to be consistent with HPS. No other etiologies for their liver disease were found. CONCLUSIONS: HPS has been recently identified as a cause of noncirrhotic portal hypertension in patients with HIV. It should be considered in the differential diagnosis of HIV patients presenting with variceal bleeding. We postulate that it may be due to intrahepatic microthrombosis or an altered hepatic fibrogenesis related to highly active antiretroviral therapy or due to HIV itself.