OBJECTIVES: This retrospective cohort study estimated the prevalence of Hepatitis C virus (HCV) and utilization of proton-pump inhibitors (PPIs) among Medicaid patients. The PPI-related economic burden among HCV patients was also determined. METHODS: Adult (18-65) patients diagnosed with HCV were identified using National Medicaid fee-for-service claims data from Jan 1 through Dec 31, 2011. HCV prevalence, comorbid GI/GERD, PPI utilization and healthcare costs per-patient-per month (PPPM) were examined. Propensity Score Matching (PSM) was performed to complete an unbiased comparison of healthcare costs among HCV patients (and a subgroup with cirrhosis) with and without PPI use. RESULTS: HCV prevalence was 0.72% (12,267/1,706,399) and the majority (93%) had a gastrointestinal (GI) condition; 36.63% had at least one PPI prescription. Among HCV patients with cirrhosis (0.12%), a liver transplant (0.01%) and end-stage liver disease (0.28%), 52.28%, 55%, and 46.38% were prescribed a PPI.  After PSM, a total of 3,362 HCV patients with and without PPI use were evaluated for cost analysis. Inpatient, emergency room, outpatient office, and pharmacy costs PPPM were significantly higher among HCV patients with PPI use compared to those without. The overall mean total costs PPPM ($3,451 vs. $2,708; p<0.001) and GI-related mean total costs PPPM ($768 versus $491; p<0.001) were significantly higher among HCV patients with PPI use, compared to those without. In a subgroup analysis of HCV patients with cirrhosis, similar trends were seen in overall total costs PPPM ($4,060 with PPI vs. $3,386 without; p=0.0457). CONCLUSIONS: When considering the categories of healthcare evaluated, total healthcare costs for HCV patients with PPI use were higher than HCV patients without PPI use, indicating a patient population with greater economic burden on the U.S. healthcare system. Similar results were seen among HCV patients with cirrhosis.