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Abstract Background Cleft lip and palate (CLP) is the most common facial birth defect worldwide and causes morphological, aesthetic, and functional problems with psychosocial implications for an individual’s life and well-being. The present systematic review and meta-analysis assessed whether the treatment of CLP impacts the oral health-related quality of life (OHRQoL) in children and adolescents in comparison to healthy controls. Methods We searched MEDLINE/PubMed, EMBASE, and PsycINFO databases using terms related to CLP, and included articles until August 2023. Observational comparison studies that assessed OHRQoL in non-syndromic CLP patients aged 8–19 years with validated scales designed to such aim or scales capable to identify aspects related to oral health compared to healthy controls were included. We used the ROBINS-I tool for risk of bias assessment. A meta-analysis of continuous variables was performed using inverse variance for pooling estimates, Standardized Mean Difference (SMD) as a summary measure, with random effects model. Heterogeneity was estimated by the I2 statistics. Sensitivity analyses included subgrouping based on the scale, risk of bias and scale domains. Meta-regression was performed under a mixed-effects model considering the variables type of scale, scale domains and risk of bias. Results Fourteen studies were included comprising 1,185 patients with CLP and 1,558 healthy controls. The direction of the effect of OHRQoL favoured the healthy group (-0.92; 95% CI:-1,55;-0,10) and I2 = 95%. After removing three studies, I2 dropped to 80%. Meta-regression showed no influence on risk of bias (p = 0.2240) but influence of scale type (p = 0.0375) and scale domains (p |