North America's first government sanctioned medically supervised injection facility (SIF) was opened during September 2003 in Vancouver, Canada. This was in response to a large open public drug scene, high rates of HIV and hepatitis C transmission, fatal drug overdoses, and poor health outcomes among the city's injection drug users. Between December 2003 and April 2005, a representative sample of 1,035 SIF participants were enrolled in a prospective cohort that required completing an interviewer-administered questionnaire and providing a blood sample for HIV testing. HIV infection was detected in 170/1007 (17%) participants and was associated with Aboriginal ethnicity (adjusted Odds Ratio [aOR], 2.70, 95% Confidence Interval [95% CI], 1.84-3.97), a history of borrowing used needles/syringes (aOR, 2.0, 95% CI, 1.37-2.93), previous incarceration (aOR, 1.87, 95% CI, 1.11-3.14), and daily injection cocaine use (aOR, 1.42, 95% CI, 1.00-2.03). The SIF has attracted a large number of marginalized injection drug users and presents an excellent opportunity to enhance HIV prevention through education, the provision of sterile injecting equipment, and a supervised environment to self-inject. In addition, the SIF is an important point of contact for HIV positive individuals who may not be participating in HIV care and treatment.