Hepatitis C virus (HCV) infection has emerged as an important factor in determining the presence and severity of cognitive impairment among individuals infected with HIV. Studies have demonstrated that coinfected patients perform worse on neuropsychological testing than monoinfected patients, typically on tests of processing speed, psychomotor speed, and learning efficiency. The mechanisms associated with this increased severity of cognitive impairment have not been identified, though a number of candidates have been proposed. This review summarizes the current literature on HIV-HCV coinfection and cognitive impairment and describes possible mechanisms mediating this relationship. Special emphasis is placed on the presence of HCV in the brain and concomitant liver disease as primary factors that may drive cognitive impairment in this population. The article concludes with suggestions for further research that are aimed toward more fully defining the neural substrates of cognitive impairment in coinfected patients.