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Objectives. We investigated potential risk factors for active injection drug use (IDU) in an inner-city cohort of patients infected with hepatitis C virus (HCV). Methods. We used log-binomial regression to identify factors independently associated with active IDU during the first 3 years of follow-up for the 289 participants who reported ever having injected drugs at baseline. Results. Overall, 142 (49.1%) of the 289 participants reported active IDU at some point during the follow-up period. In a multivariate model, being unemployed (prevalence ratio [PR] = 1.93; 95% confidence interval [CI] = 1.24, 3.03) and hazardous alcohol drinking (PR = 1.67; 95% CI = 1.34, 2.08) were associated with active IDU. Smoking was associated with IDU but this association was not statistically significant. Patients with all 3 of those factors were 3 times as likely to report IDU during follow-up as those with 0 or 1 factor (PR = 3.3; 95% CI = 2.2, 4.9). Neither HIV coinfection nor history of psychiatric disease was independently associated with active IDU. Conclusions. Optimal treatment of persons with HCV infection will require attention to unemployment, alcohol use, and smoking in conjunction with IDU treatment and prevention. [ABSTRACT FROM AUTHOR]