Objective: To test the hypothesis that malocclusion does not have an independent and negative effect on quality of life of adolescents. Materials and Methods: The cross-sectional design study comprised a sample of 519 children, aged 11 to 14 years, attending public schools in Osorio, a city in southern Brazil. One calibrated examiner carried out clinical examinations and recorded dental caries (decayed/missing/filled teeth), malocclusion (Dental Aesthetic Index), and dental trauma. Participants completed the Brazilian version of the Child Perceptions Questionnaire (CPQ _11–14 ), Impact Short Form, and their parents or guardians answered questions about socioeconomic status. Simple and multivariate linear regressions were performed to assess covariates for the overall CPQ _11–14 scores. Results: Greater impacts on oral health–related quality of life were observed for girls ( P = .007), children with a lower household income ( P = .016), those living in nonnuclear families ( P < .001), and those with more decayed/missing/filled teeth ( P = .001). Malocclusion was also associated with oral health–related quality of life: the severity of malocclusion was significantly related to higher scores of CPQ _11–14 even after scores were adjusted for control variables. CPQ _11–14 increased by approximately 1 point for each increase in the severity of malocclusion. Conclusions: Malocclusion has a negative effect on adolescents' quality of life, independent of dental caries or traumatic dental injuries. Socioeconomic inequalities and clinical conditions are important features in adolescents' quality of life.