Research increasingly supports the neurovirulence of chronic infection with the hepatitis C virus (HCV). For example, HCV infection has been associated with neuropsychological impairment in several ability areas, including psychomotor skills. This study aimed to examine whether HCV-associated neuropsychological impairment is predictive of declines in the independent performance of physical (PADLs) and instrumental (IADLs) activities of daily living. A total of 106 volunteers with HCV infection completed a comprehensive neuropsychological, medical, and psychiatric research evaluation. As compared to 30 HCV-seronegative comparison participants, the HCV-infected group reported significantly greater declines in both PADLs and IADLs. Within the HCV cohort, individuals with impaired speed of information processing reported significantly greater IADL declines, whereas impaired fine-motor coordination was associated with declines in both IADLs and PADLs. In a series of regression analyses, impaired speed of information processing and depressive symptoms (as measured by the Beck Depression Inventory) were the only independent predictors of IADL declines, whereas general affective distress (as measured by the Profile of Mood States), sex, and fine-motor coordination impairment were predictive of declines in PADLs. Although the clinical assessment of HCV typically emphasizes both affective (e.g., depression) and physical factors, findings from the present study suggest that cognitive impairment is an important contributor to everyday functioning in persons living with HCV infection and therefore warrants consideration in clinical and research evaluations.