The aim of the study was to determine whether infection with the hepatitis C virus (HCV) is associated with cognitive impairment beyond the effects of prevalent comorbidities and a history of substance use disorder (SUD). Adult veterans were recruited from the Portland Veterans Affairs Medical Center into three groups: (1) HCV+/SUD+ (n = 39), (2) HCV+/SUD− (n = 24), and (3) HCV−/SUD− (n = 56). SUD+ participants were in remission for ≥90 days, while SUD− participants had no history of SUD. Groups did not significantly differ in terms of rates of psychiatric or medical comorbidities. Procedures included clinical interviews, medical record reviews, and neuropsychological testing. Significant group differences were found in the domains of Verbal Memory, Auditory Attention, Speeded Visual Information Processing, and Reasoning/Mental Flexibility (p ≤ .05). Post hoc comparisons indicated that HCV+/SUD− patients performed significantly worse than HCV−/SUD− controls on tests measuring verbal learning, auditory attention, and reasoning/mental flexibility, but only HCV+/SUD+ patients did worse than HCV−/SUD− controls on tests of speeded visual information processing. Results indicate that chronic HCV is associated with cognitive impairment in the absence of a history of SUD. The most robust deficits appear to be in verbal learning and reasoning/mental flexibility. (JINS, 2009, 15, 69–82.)