Background. Despite the widely noted increase in crystal methamphetamine (CM) use, there are few studies on circumstances of first CM use or correlates of use among high-risk populations (e.g. street-involved youth). Methods. Street-involved youth in Vancouver, Canada, were enrolled in the At-Risk Youth Study (ARYS) prospective cohort. Extensive outreach produced a representative sample of Vancouver street youth who use illicit drugs. We examined circumstances of first CM use and factors associated with CM use among the cohort. Results. Among 478 participants, 339 (70.9%) had used CM previously. Despite intensive covariate adjustment, a history of CM use was associated independently with having initiated injection drug use [OR = 3.15 (95% CI: 1.89 - 5.2); p < 0.001]. Among those who had used CM, route of first administration included: 11 (3.2%) oral ingestion; 25 (7.4%) injected; 105 (31.0%) snorted; 231 (68.1%) smoked. The proportion of respondents reporting current CM injection was significantly greater than the proportion reporting injection as the route for first CM use (18.3% vs. 7.4%; McNemar's test p < 0.001). Ability to obtain CM the first time was reported as 'very easy' or 'easy' by 93.5% and 5.3% of participants, respectively. Conclusions. Crystal methamphetamine use was independently associated with injection drug use, and significant increases in injecting as the primary mode of administration were observed when patterns of use were considered longitudinally. The easy accessibility of CM and its common use during transition into injection drug use demonstrate the need for innovative drug policy to address this growing concern. [Wood E, Stoltz J-A, Zhang R, Strathdee SA, Montaner JSG, Kerr T. Circumstances of first crystal methamphetamine use and initiation of injection drug use among high-risk youth. Drug Alcohol Rev 2008;27:270-276]