BACKGROUND AND AIMS: Abnormal liver enzymes (LEs) are common in those infected with human immunodeficiency virus (HIV). Histologic data on those with abnormal LE without viral hepatitis are lacking. METHODS: HIV-positive subjects without hepatitis C virus, hepatitis B virus, alcohol abuse, and diabetes mellitus with more than 1 abnormal LE, defined as 1.25 ULN in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase, over 6 months were included. Subjects underwent a 2-hour oral glucose tolerance test, fasting lipids, insulin and glucose for insulin resistance (IR) by homeostasis model assessment for insulin resistance (HOMA-IR) and dual-energy X-ray absorptiometry for fat distribution. Biopsies were read blindly to clinical data, and scored by Ishak histologic activity index for inflammation and fibrosis and NAFLD activity score. RESULTS: Fourteen patients underwent biopsy. All were on highly active antiretroviral therapy with undetectable HIV RNA and mean CD4 614. The histologic activity index scores for inflammation and fibrosis were 3.43(1.4) and 1.71(1.26), respectively, and 2 patients had advanced fibrosis (bridging fibrosis/cirrhosis). The majority (65%) of patients had steatosis: grade 1: 21%, grade 2: 28%, and grade 3: 14%. Hepatocyte ballooning was seen in 7 (40%) but nonalcoholic steatohepatitis (NASH) was diagnosed only in 4 (26%). NAFLD activity score of all biopsies of 3.07 (2.2; range, 0 to 5). HOMA-IR was higher in those with compared with those without steatosis (3.52 vs. 1.91; P=0.11) and highest in those with NASH (4.89). Using multivariate logistic regression, only increased γ-glutamyl transpeptidase (P=0.0009) predicted steatosis whereas HOMA-IR (P=0.0046) predicted NASH. CONCLUSIONS: Although steatosis is common in HIV patients with abnormal LE without diabetes mellitus, alcohol, or viral hepatitis coinfection, NASH was observed in only 26%. The only clinical or laboratory feature associated with biopsy proven steatosis and NASH were γ-glutamyl transpeptidase and a calculated measure of insulin resistance, respectively. Further studies are needed in this population to determine the long-term clinical significance.