SummaryBackgroundMalocclusions in adolescents might have a negative impact on oral health-related quality of life (OHRQoL). Potential confounding variables (confounders) such as age, gender, caries, and socioeconomic status may skew the real relationship between malocclusions and OHRQoL.ObjectivesTo analyse the effect of malocclusions in adolescents on OHRQoL, when controlled for potential confounders.Search methodsFive databases (PubMed, Cochrane Library, Cinahl, Scopus, and Web of Science) were searched up to 15 June 2022.Selection criteriaStudies in which OHRQoL in 10–19-year olds with and without malocclusions were compared.Data collection and analysisScreening, data extraction, and quality assessments were performed by four investigators independently. Risk of bias was assessed according to the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) guidelines. To be included, studies had to control for confounders. Certainty of evidence was assessed with GRADE.ResultsThirteen cross-sectional studies with low and moderate risk of bias were included in the qualitative synthesis. Four of these were also included in the quantitative synthesis (meta-analysis). The 13 studies in the qualitative synthesis displayed a large variation among the indices used for malocclusion ratings, as well as in instruments measuring OHRQoL. There was moderate quality of evidence that malocclusions have a negative effect on OHRQoL. The four articles included in the quantitative synthesis (meta-analysis) measured malocclusions with DAI and OHRQoL with CPQ 11–14 short form. There was moderate quality of evidence that malocclusions have a negative effect on OHRQoL (RR/PR 1.15, 95% CI 1.12–1.18, 3672 participants).ConclusionsThere is moderate quality of evidence that malocclusions in adolescents have a negative impact on OHRQoL, after taking relevant confounders into consideration. Future studies should ideally use standardized measures for malocclusion ratings and OHRQoL.RegistrationPROSPERO. CRD42020186152.