Objective: The present study examines knowledge of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) among individuals with serious mental illness. Methods: Two hundred and thirty-six people answered questions regarding their knowledge of HIV and HCV. Results: The total correct score for the set of HIV items (79%) was significantly higher than the total correct score for the set of HCV items (70%). Although the majority of demographic variables were not significantly associated with knowledge, individuals who had been previously screened for FIN answered significantly more HIV and HCV questions accurately. Conclusions: These results indicate that there is a specific gap in knowledge about HCV among individuals with serious mental illness, suggesting the need for intervention development to increase disease-related knowledge.