BACKGROUND: Injection drug use (IDU) is considered the major risk factor for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection. We examined risk factors for HIV/HCV coinfection in a region with a low reported rate of IDU. METHODS: We identified 146 HIV/HCV coinfected patients in Jackson, Mississippi. Medical records were reviewed for demographics, social history, and risk factors for HIV and HCV acquisition. A randomly selected group of HIV-monoinfected patients from the same clinic served as a control group. RESULTS: History of IDU (P < 0.0001), crack cocaine use (P < 0.0001), incarceration (P < 0.0001), and syphilis (P < 0.0001) were significantly associated with HCV infection in this cohort of HIV patients. However, the reported rate of IDU (32.5%) is lower than other published HIV/HCV-infected cohorts. CONCLUSIONS: HIV/HCV patients in Mississippi are less likely to report a history of IDU than other coinfected populations, suggesting an alternative means of HCV transmission. Further studies are needed to examine the role of syphilis, crack cocaine use, and incarceration as risk factors for HCV infection in this population of HIV patients. © Copyright 2009 Southern Society for Clinical Investigation.