Comorbidities may affect the decision to treat chronic hepatitis C virus (HCV) infection. We undertook this study to determine the prevalence of these conditions in the HCV-infected persons compared with HCV-uninfected controls. Demographic and comorbidity data were retrieved for HCV-infected and -uninfected subjects from the VA National Patient Care Database using ICD-9 codes. Logistic regression was used to determine the odds of comorbid conditions in the HCV-infected subjects. HCV-uninfected controls were identified matched on age, race/ethnicity and sex. We identified 126 926 HCV-infected subjects and 126 926 controls. The HCV-infected subjects had a higher prevalence of diabetes, anaemia, hypertension, chronic obstructive pulmonary disease (COPD)/asthma, cirrhosis, hepatitis B and cancer, but had a lower prevalence of coronary artery disease and stroke. The prevalence of all psychiatric comorbidities and substance abuse was higher in the HCV-infected subjects. In the HCV-infected persons, the odds of being diagnosed with congestive heart failure, diabetes, anaemia, hypertension, COPD/asthma, cirrhosis, hepatitis B and cancer were higher, but lower for coronary artery disease and stroke. After adjusting for alcohol and drug abuse and dependence, the odds of psychiatric illness were not higher in the HCV-infected persons. The prevalence and patterns of comorbidities in HCV-infected veterans are different from those in HCV-uninfected controls. The association between HCV and psychiatric diagnoses is at least partly attributable to alcohol and drug abuse and dependence. These factors should be taken into account when evaluating patients for treatment and designing new intervention strategies.