Aim: To assess the diagnostic value of modified cutoffs for aspartate aminotransferase to platelet ratio index (APRI) to predict significant liver fibrosis in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) patients. Patients and Methods: This retrospective cross‐sectional study included consecutive patients with HIV/HCV co‐infection who underwent percutaneous liver biopsy. The accuracy of APRI for the diagnosis of significant fibrosis (F2/F3/F4 METAVIR) was evaluated by estimating the positive and negative predictive values (PPV and NPV respectively) and by measuring the area under the receiver operating characteristics curve (AUROC). Results: One hundred and eleven patients were included (73% men, mean age 40.2±7.8 years). Significant fibrosis was observed in 45 patients (41%). To discriminate these subjects, the AUROC of APRI was 0.774±0.045. An APRI≥1.8 showed a PPV of 75% for the presence of significant fibrosis, and an index <0.6 excluded significant fibrosis with an NPV of 87%. If biopsy indication was based only on APRI and restricted to scores in the intermediate range (≥0.6 and <1.8), 46% of liver biopsies could have been avoided as compared with 40% using the classical cutoffs. Conclusion: APRI with adjusted cutoffs can predict significant liver fibrosis in patients with HIV/HCV co‐infection and might obviate the need to perform a biopsy in a considerable percentage of those subjects.