HIV/HCV co-infection is becoming one of the main causes of death in HIV+ persons. We determined quality of life, clinical symptoms and health care utilization in HIV mono-infected and HIV/HCV co-infected chronic drug users. After consenting 218 HIV+ drug users, a physical examination and questionnaires on demographics, quality of life, drugs of abuse, and healthcare utilization were completed. Blood was drawn for HCV status, CD4 cell count, HIV viral load, CBC and chemistry. HIV/HCV co-infected participants had significantly higher risk of having poorer perceived outlook and health, presented significantly more frequent depression and physical symptoms, and used significantly more healthcare services than those infected with HIV only, after adjusting for age, gender, ethnicity, CD4 cell count, and viral load. Diminished quality of life in the HIV/HCV co-infected group was explained by increased frequency of depression, physical symptoms, healthcare utilization, and poor access to HCV treatment in this population.