OBJECTIVES Whether new biomarkers contribute significantly to the existing, simple noninvasive test (comprising of routine laboratory parameters such as the AST to platelet ratio index (APRI)) for predicting liver fibrosis remains unknown. METHODS We measured 7 biomarkers in 91 patients with chronic hepatitis C (CHC): haptoglobin, apolipoprotein A1, α2-macroglobulin, hyaluronic acid, type III procollagenic peptide, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-1. RESULTS The "multibiomarker" score (based on regression coefficients of significant biomarkers) is an independent predictive factor for significant fibrosis [APRI-adjusted odds ratio, 2.41 (95% CI, 1.28 to 4.55)]. However, the incorporation of the multibiomarker score into the APRI resulted in only a small diagnostic improvement [0.83 (95% CI, 0.74 to 0.92) vs. 0.79 (0.69 to 0.89); p=0.19]. CONCLUSIONS For assessing significant fibrosis in individual CHC patients, the 7 contemporary biomarkers that we studied add only modestly to the readily available, simple noninvasive index.