BACKGROUND. In single-institution multireader studies, the liver surface nodularity (LSN) score accurately detects advanced liver fibrosis and cirrhosis and predicts liver decompensation in patients with chronic liver disease (CLD) from hepatitis C virus (HCV). OBJECTIVE. The purpose of this study was to assess the diagnostic performance of the LSN score alone and in combination with the (FIB-4; fibrosis index based on four factors) to detect advanced fibrosis and cirrhosis and to predict future liver-related events in a multiinstitutional cohort of patients with CLD from HCV. METHODS. This retrospective study included 40 consecutive patients, from each of five academic medical centers, with CLD from HCV who underwent nontargeted liver biopsy within 6 months before or after abdominal CT. Clinical data were recorded in a secure web-based database. A single central reader measured LSN scores using software. Diagnostic performance for detecting liver fibrosis stage was determined. Multivariable models were constructed to predict baseline liver decompensation and future liver-related events. RESULTS. After exclusions, the study included 191 patients (67 women, 124 men; mean age, 54 years) with fibrosis stages of F0–F1 (n = 37), F2 (n = 44), F3 (n = 46), and F4 (n = 64). Mean LSN score increased with higher stages (F0–F1, 2.26 ± 0.44; F2, 2.35 ± 0.37; F3, 2.42 ± 0.38; F4, 3.19 ± 0.89; p < .001). The AUC of LSN score alone was 0.87 for detecting advanced fibrosis (≥ F3) and 0.89 for detecting cirrhosis (F4), increasing to 0.92 and 0.94, respectively, when combined with FIB-4 scores (both p = .005). Combined scores at optimal cutoff points yielded sensitivity of 75% and specificity of 82% for advanced fibrosis, and sensitivity of 84% and specificity of 85% for cirrhosis. In multivariable models, LSN score was the strongest predictor of baseline liver decompensation (odds ratio, 14.28 per 1-unit increase; p < .001) and future liver-related events (hazard ratio, 2.87 per 1-unit increase; p = .03). CONCLUSION. In a multiinstitutional cohort of patients with CLD from HCV, LSN score alone and in combination with FIB-4 score exhibited strong diagnostic performance in detecting advanced fibrosis and cirrhosis. LSN score also predicted future liver-related events. CLINICAL IMPACT. The LSN score warrants a role in clinical practice as a quantitative marker for detecting advanced liver fibrosis, compensated cirrhosis, and decompensated cirrhosis and for predicting future liver-related events in patients with CLD from HCV.