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Liver biopsy, the gold standard for assessing hepatitis C virus (HCV)-related fibrosis, is invasive and prone to complications. Our aim was to determine the operating characteristics of a non-invasive index of biochemical markers for the prediction of fibrosis in patients with HIV/HCV co-infection.In a cross-sectional, cohort study in a French tertiary-care hospital 130 HIV/HCV-co-infected patients with a liver biopsy and serum were tested for markers of liver fibrosis.An index incorporating age, sex, α2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin, and γ-glutamyl-transpeptidase (GGT), derived using multivariate logistic regression, was compared with liver histology. HIV-specific indices including the CD4 cell count and HIV-RNA load were also constructed. The diagnostic values of the indices were compared using receiver operating characteristic (ROC) curves.Septal fibrosis (F2–F4) by the METAVIR classification.By multivariate analysis, the most informative markers were α2-macroglobulin, apolipoprotein A1, GGT, and sex. The area under the ROC curve of the five-marker index was 0.856 ± 0.035; not significantly different from the HIV-specific indices. On a scale from zero to 1.00, the five-marker index had a positive predictive value of 86% for scores greater than 0.60, and a negative predictive value of 93% for scores of 0.20 or less. These thresholds could reduce the necessity for liver biopsy by 55% while maintaining an accuracy of 89%.An index including five biochemical markers accurately predicts significant fibrosis in patients with HIV/HCV co-infection, and may substantially reduce the necessity for liver biopsy.