OBJECTIVES: To assess the direct healthcare and indirect work-loss cost burden of chronic hepatitis C virus (HCV) infection and stratify the economic burden by disease severity. METHODS: Health insurance claims from 60 self-insured US companies and disability data for employees in 29 of these companies covering the period 01/2001-09/2011 were analyzed. Adult patients with ≥2 diagnosis claims of chronic HCV infection and no HIV diagnosis were selected. A 6-month baseline period of continuous eligibility preceding HCV diagnosis was imposed. HCV patients were stratified into groups of non-cirrhotic, compensated cirrhotic, and end-stage liver disease (ESLD). HCV patients were matched 1:1 with non-HCV controls using an exact factors and propensity score matching algorithm. Matched cohorts were compared for direct (pharmacy dispensings and medical services) and indirect (disability and medically related absenteeism) costs using per-patient per-year (PPPY) cost differences.  RESULTS: Both cohorts (N=9,841 for each) were well matched with respect to age (mean=52 years), gender (female=39%), Quan-Charlson comorbidity index (mean=0.5), share of employees with disability coverage (26%), and non-HCV related co-morbidities. HCV patients incurred significantly greater direct and indirect costs relative to non-HCV patients (PPPY direct costs: $16,721 vs. $6,063, cost difference [95% CI] = $10,503 [9,683-11,361], P<0.001; PPPY indirect costs: $3,310 vs. $1,723, cost difference [95% CI] = $1,523 [1,248-1,794], P<0.001). The direct incremental cost burden associated with HCV increased with disease severity (incremental direct cost [95% CI]: non-cirrhotic HCV = $5,536 [4,844-6,333]; compensated cirrhotic = $6,833 [5,326-8,474]; ESLD = $22,466 [20,182-24,729], P<0.001 for all comparisons vs. matched non-HCV controls in each sub-category). Among the subset of employees with disability coverage, the incremental indirect cost burden associated with HCV also increased with disease severity. CONCLUSIONS: Chronic HCV infection was associated with significant direct healthcare and indirect work-loss cost burdens. The magnitude of the cost burden increased with disease severity.