To evaluate the association between discrimination based on sexual orientation and oral health-related quality of life (OHRQoL) in adolescents. This was a cross-sectional study nested in a cohort performed in southern Brazil. The baseline assessment was carried out in 2010 with a sample of preschoolers (1 to 5 years). Subsequently, these individuals were reassessed, and for the present study, only the data from the final follow-up in 2020 were considered. OHRQoL was assessed by the short version of the Child Perceptions Questionnaire 11-14 (CPQ11-14). The discrimination due to sexual orientation was measured using item 10 of the Olweus Bully/Victim Questionnaire. Sociodemographic (sex, age, skin color, maternal education, household income) psychosocial (sense of coherence), and clinical variables (untreated dental caries) were also evaluated. Multilevel Poisson regression analysis was performed to verify the associations. Results are present as rate ratio (RR) and 95% confidence interval (95% CI). A total of 429 adolescents were evaluated - about 67.1% of those assessed at baseline. The prevalence of discrimination due to sexual orientation was 3.3%. Adolescents who reported suffering episodes of discrimination due to sexual orientation presented overall CPQ11-14 scores 16% higher (RR 1.16, 95%CI 1.01-1.36) than their counterparts. Adolescents who reported suffering episodes of discrimination due to sexual orientation presented poorer OHRQoL.