Research shows that sexual minorities are at greater risk for illicit substance use and related harm than their heterosexual counterparts. This study examines a group of active drug users to assess whether sexual identity predicts increased risk of substance use and harm from ecstasy, ketamine, alcohol, marijuana, cocaine and crack. Structured interviews were conducted with participants aged 15 years and older in Vancouver and Victoria, BC, Canada, during 2008-2012. Harm was measured with the World Health Organization s AUDIT and ASSIST tools. Regression analysis controlling for age, gender, education, housing and employment revealed lesbian, gay or bisexual individuals were significantly more likely to have used ecstasy, ketamine and alcohol in the past 30 days compared to heterosexual participants. Inadequate housing increased the likelihood of crack use among both lesbian, gay and bisexuals and heterosexuals, but with considerably higher odds for the lesbian, gay and bisexual group. Lesbian, gay and bisexual participants reported less alcohol harm but greater ecstasy and ketamine harm, the latter two categorised by the ASSIST as amphetamine and hallucinogen harms. Results suggest encouraging harm reduction among sexual minority, high-risk drug users, emphasising ecstasy and ketamine. The impact of stable housing on drug use should also be considered.