In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Few studies investigated noninvasive markers of liver fibrosis in hepatitis C virus (HCV) patients with normal alanine aminotrasferase (NALT). Eighty HCV patients with NALT and 164 HCV patients with elevated alanine aminotrasferase (EALT) who underwent a diagnostic liver biopsy were evaluated for AST-to-platelet ratio, Forns' index, AST-to-ALT ratio (AAR), Fibrotest and the recently proposed Fibroindex, using liver histology as reference standard. The primary end-point was the detection of significant fibrosis (> or =F2). Performance of noninvasive markers was expressed as specificity, sensitivity and positive (PPV) and negative (NPV) predictive value, accuracy and area under the receiver operating characteristic curve (AUROC). All noninvasive markers for liver fibrosis tested showed a poorer performance in NALT group than in EALT group. Overall, Fibrotest had the best performance in NALT group, as showed by AUROC of 0.70 and 73.5% accuracy. Performance of AAR, Forns' index and Fibroindex was poor in NALT group and it was significantly lower than in EALT group for Forns and Fibroindex (AUROC 0.6 vs 0.76 and 0.58 vs 0.74, respectively, P = 0.05). In NALT patients, PPV was high for all noninvasive markers (>87%) except for AAR, while NPV was low (<65%), thus none of them was able to reliably exclude significant fibrosis. In conclusion, performance of noninvasive-markers is significantly reduced in HCV patients with NALT. Liver biopsy may still be needed for many of these cases to correctly stage liver fibrosis. Specific noninvasive tools and possibly combination of markers should be developed and validated in this clinical setting.