Purpose <p>Oral health-related quality of life (OHRQoL) is a&#xa0;patient-reported outcome measure (PROM) that assesses patients’ subjective perception of their oral health status. Previous studies assessing the influence of malocclusions on OHRQoL revealed inconsistent results. This cross-sectional multicenter cohort study aimed to investigate the impact of general orthodontic treatment need (OTN) and of specific anterior malocclusions on OHRQoL and its subdomains in children and adolescents with class&#xa0;II malocclusion.</p> Methods <p>This study included 321 patients with class&#xa0;II malocclusion who required an initial orthodontic diagnosis. OHRQoL was assessed using the German version of the Child Oral Health Impact Profile (COHIP-G19). OTN was evaluated using the Dental Aesthetic Index (DAI) and the Index of Orthodontic Treatment Need (IOTN). To determine specific anterior malocclusions, overjet, overbite, anterior crowding, and anterior spacing were analyzed. Multiple linear regression analysis was performed to examine the effects of OTN and of the anterior malocclusions on OHRQoL and its subdomains, adjusted for demographic confounders (age, gender, and socioeconomic status).</p> Results <p>High values for OTN were significantly associated with poorer OHRQoL in patients with class&#xa0;II malocclusion. Multiple regression showed a&#xa0;significant effect of overjet and anterior crowding in the upper jaw on OHRQoL. No statistically significant associations were found between OHRQoL and anterior open bite, deep bite, or anterior spacing.</p> Conclusion <p>High general OTN as well as specific anterior malocclusions such as increased overjet and anterior crowding showed significant associations with OHRQoL in children and adolescents with class&#xa0;II malocclusion. In addition, other unmeasured factors likely play a&#xa0;distinctive role in determining OHRQoL.</p>