Introduction & Aim: Patients with untreated chronic hepatitis C (CHC) infection are at increased risk of developing a liver-related outcome. Despite the availability of simplified direct-acting antiviral therapy, the prevalence of CHC remains unchanged in many industrialized countries. Biomarkers that can predict which chronic liver disease patients with inflammatory injury are at greatest risk of developing a clinical outcome are required. In a subgroup from The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (HALT-C) (ClinicalTrials.gov #NCT00006164), we investigated PRO-C3 as a marker of active fibrogenesis to predict liver-related outcomes and CPa9-HNE as a marker of neutrophil activity to predict outcomes related to hepatic decompensation. Methods: The fibrogenesis marker, nordicPRO-C3™ measuring the formation of type III collagen, and nordicCPa9-HNE™, measuring human neutrophil elastase degraded calprotectin secreted by activated neutrophils, were assessed in stored serum samples. Kaplan-Meier analysis was used to examine the event-free survival probability when stratifying PRO-C3 into below and above the lower quartile (Q1=27.6 ng/mL) and CPa9-HNE into below and above median (median=1850.5 ng/mL). Cox proportional hazard regression analysis was used to investigate the hazard ratio (HR) for developing a liver-related outcome with either high or low PRO-C3 or CPa9-HNE. Liver-related outcomes include death, hepatocellular carcinoma (HCC), Child-Pugh score ≥7 (CTP≥7), variceal hemorrhage, ascites, bacterial peritonitis, and encephalopathy. Data provided by NIDDK CR, a program of the National Institute of Diabetes and Digestive and Kidney Diseases. Results: This subgroup included 340 patients (65% male) from the HALT-C cohort (median age 50 years; BMI 29.4 kg/m2). Eighty-nine patients (26%) had a liver-related outcome over a median follow-up of 1037 days (Q1-Q3: 619-1383). When stratifying patients into baseline PRO-C3 above and below the Q1 cut-off, the HR for developing an outcome (including death, HCC, and CTP≥7) was 4.43 times higher (95% CI= [1.92-10.19], p<0.001) in patients with high PRO-C3 compared to low. CPa9-HNE does not predict these selected outcomes. When stratifying patients into baseline CPa9-HNE above and below the median cut-off, the HR for developing an outcome related to hepatic decompensation (variceal hemorrhage, ascites, bacterial peritonitis, and encephalopathy) was 5.90 times higher (95% CI: [1.31-26.64], p<0.01) in patients with low CPa9-HNE compared to high. PRO-C3 does not predict outcomes related to these hepatic decompensation outcomes. Conclusion: Active fibrogenesis, determined by PRO-C3, is associated with an increased risk of a liver-related outcome, and low neutrophil activity, determined by CPa9-HNE, is associated with an increased risk of outcomes related to hepatic decompensation in patients with untreated CHC infection. Pro-fibrogenic markers and immune cell activity markers could have prognostic value in other chronic liver disease patients. Their predictive value, however, varies based on the specific liver-related outcome. It is therefore crucial to account for this variability when searching for noninvasive biomarkers.