Background There is a co-occurrence of adolescents' substance use and sexual practices, with an important impact on their health and health behaviours; however, limited research is conducted with adolescents. The aim of this study was to estimate the prevalence of substance use (alcohol and/or other substances) in sexual contexts and to identify its associated factors among adolescents, comparing boys and girls. Methods Cross-sectional study with data from 6352 adolescents aged 14----18years from the DESKcohort project. Prevalence of alcohol and/or other substance use in sexual contexts (OSUSC) stratified by sex were calculated, according to axes of inequality, psychosocial factors, and sexual health and health variables. Poisson regression models with robust variance were calculated to analyse potential associations with independent variables. Results Girls (51.4% of the sample) reported a higher prevalence of alcohol use in sexual contexts than boys (43.9% vs 33.9%, P Conclusions These findings suggest that substance use in sexual contexts reflects a broader pattern of co-occurring risky behaviours rather than intentional sexualised substance use. Some vulnerable groups include girls, adolescents with a minority sexual orientation, and students with disadvantaged SEPs. These findings underscore the need for holistic interventions targeting adolescents' health, addressing substance use and sexual risk behaviours simultaneously to reduce potential consequences such as unplanned pregnancies and sexually transmitted infections.