In North America, street youths are generally considered at very high risk of injection drug use. To estimate the incidence rate of injection drug use in this population and to identify predictors of injection drug use, we conducted the present analysis. Among participants to a cohort study initiated in January 1995, we selected subjects who had never injected at study entry and had completed at least one follow-up questionnaire. Predictors of initiation were identified using Cox proportional hazard regression models. Among the 415 never injectors (mean age at entry 19.5 years), 74 had initiated injection by January 2000 (incidence rate 8.2 per 100 person-years). Independent predictors of initiation were recent episode of homelessness; age younger than 18 years; being tattooed; recently using hallucinogens, heroin, and cocaine/crack/freebase; having a friend who injects drugs; and having ever experienced extrafamilial sexual abuse. This study showed that injection drug use is frequent among street youths, but prevention appears possible.