Background. We determined temporal trends (1985-2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne). Methods. Using population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985-2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar- time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk. Results. Among 1391 initially HCV-negative participants followed prospectively (1644.5 person-years of observation [PYO]), 371 HCV incident infections resulted in an overall incidence of 22.6 per 100 PYO (95% confidence interval [CI], 20.4-25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 [95% CI,.8-. 9]) in the multivariable model. Conclusions. Differences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America.