Objective: To compare oral health-related quality of life (OHRQoL) before treatment of adults with unilateral cleft lip and palate (UCLP) and surgical Class III malocclusion, and to consider if clefts needing different orthodontic treatment protocols could influence people’s self-perception. Design: Cross sectional. Setting: Cleft Lip and Palate Center and Clinic of Orthognathic Surgery from a School of Dentistry. Participants: A sample of adults with repaired nonsyndromic UCLP (n = 52) which was age- and sex-matched with a noncleft Class III malocclusion sample seeking orthognathic surgery (n = 51). In turn, the cleft group was subdivided according to treatment planning into nonsurgical orthodontic and surgical orthodontic approaches. Main Outcome Measure: The whole sample was assessed using the short-form oral health impact profile (OHIP-14), with higher scores indicating a poorer OHRQoL. Statistical comparisons were performed with Mann-Whitney U and Kruskal-Wallis tests, and effect size. Bonferroni adjustment was used for post hoc tests ( P < .017). Results: The OHIP-14 scores of the UCLP and Class III groups were significantly different ( P = .001, η2 = 0.108), and higher in Class III. The largest commitment was in the physical disability, physical pain, and psychological disability domains. In addition, no differences were found when the UCLP treatment planning was considered. Conclusion: Surgical Class III malocclusion have a poorer OHRQoL when compared to patients with UCLP, irrespective of whether they are treated surgically or orthodontically. Therefore, the greater commitment of OHRQoL appears to be influenced by the etiology of Class III, and not by treatment plan.