Background: Street-involved youth are at high risk for experimenting with injection drug use; however, little attention has been given to identifying the factors that predict progression to on-going injecting. Methods: Logistic regression was used to identify factors associated with progression to injecting weekly on a regular basis among a Canadian cohort of street-involved youth. Results: Among our sample of 405 youth who had initiated injecting at baseline or during study observation, the median age was 22 years (interquartile range [IQR] = 21–24), and 72% (293) reported becoming a regular injector at some point after their first injection experience. Of these, the majority (n = 186, 63%) reported doing so within a month of initiating injection drug use. In multivariate analysis, the drug used at the first injection initiation event (opiates vs. cocaine vs. methamphetamine vs. other; all p > 0.05) was not associated with progression; however, younger age at first injection (adjusted odds ratio [AOR] = 1.13), a history of childhood physical abuse (AOR = 1.81), prior regular use of the drug first injected (AOR = 1.77), and having a sexual partner present at the first injection event (AOR = 2.65) independently predicted progression to regular injecting. Conclusion: These data highlight how quickly youth progress to become regular injectors after experimentation. Findings indicate that addressing childhood trauma and interventions such as evidence-based youth focused addiction treatment that could prevent or delay regular non-injection drug use, may reduce progression to regular injection drug use among this population.