To determine whether perceived discrimination of being a sexual minority is associated with substance use and mental health outcomes among adolescents in five urban sites across the world. Data were from female and male adolescents aged 15-19 from Baltimore, Maryland, USA; New Delhi, India; Ibadan, Nigeria; Johannesburg, South Africa; and Shanghai, China (N=2,339) who participated in Phase 2 of the Well-being of Adolescents in Vulnerable Environments (WAVE) study, which utilized respondent-driven sampling to recruit adolescents for a cross-sectional survey from economically disadvantaged neighborhoods in each site. The prevalence and association of sexual orientation and discrimination, substance use (alcohol, tobacco, marijuana, and illicit drugs), and mental health outcomes (depression and suicidal ideation and attempts) among sexual minority adolescents in the 5 cities is described. Multivariate logistic regression models were used to estimate associations of sexual orientation and discrimination with substance use and mental health outcomes among adolescents in each city. Across all sites, 18.4% of the sample identified as a sexual minority, which ranged from 16% in Johannesburg to 37% in Ibadan. In the bivariate analysis, the prevalence of at least one substance use and/or mental health outcome was significantly higher among sexual minority adolescents than heterosexual adolescents across all 5 cities. Sexual minority youth in Baltimore had significantly worse substance use and mental health outcomes across 6 of the 7 outcomes observed. With the exception of New Delhi, adolescents who perceived discrimination were also significantly more likely to use substances and have poor mental health outcomes, regardless of their sexual orientation. In the logistic regression, a pattern of multiplicative effects emerged across sites, with discrimination compounding the effects of sexual minority status. For example, in Baltimore, sexual minority youth were 3.79 times more likely to report alcohol use in the last 30 days (p<.01; 1.80 – 7.98); yet if they experienced discrimination, they were 8.59 times more likely to report alcohol use in the last 30 days (p<.001; 5.10 – 14.48). Similar patterns were observed for other substance use and mental health outcomes. Sexual minority adolescents, specifically those who perceive discrimination, are at higher odds of substance use and poor mental health outcomes across different urban sites around the world. While the number of outcomes that are impacted is not stable across cities, the pattern is the same. This demonstrates the impact of sexual minority status and subsequent discrimination on the psychological well-being of adolescents, irrespective of the cultural context. Interventions need to focus on not only improving outcomes for sexual minorities, but also reducing discrimination on behalf of others, in both developing and developed countries.