Most of the estimated 125,000 injection drug users (IDUs) in Canada use illicit opioids and are outside treatment (i.e., methadone maintenance treatment). Empirical data suggest that illicit opioid users outside treatment are characterized by various health and social problem characteristics, including polydrug use, physical and mental morbidity, social marginalization, and crime. Although required for evidence-based programming, systematic information on this specific substance-user population is sparse in Canada to date. This article presents and compares key characteristics of population of illicit opioid users outside treatment in five cities across Canada (OPICAN cohort). Overall, the majority of OPICAN participants regularly used both a variety of illicit opioids and cocaine or crack, reported physical and mental health (e.g., mood disorder) problems, lacked permanent housing, were involved in crime, and had their “ideal” treatment not available to them. However, key local sample differences were shown, including patterns of heroin versus prescription opioid use and levels of additional cocaine versus crack use as well as indicators of social marginalization. Illicit opioid user population across Canada differ on key social, health, and drug use indicators that are crucial for interventions and are often demonstrated between larger and smaller city sites. Differentiated interventions are required.