The purpose of this study was to investigate the effect of orthodontic treatment on oral health-related quality of life (OHRQoL) in groups of standard patients with severe malocclusions; cleft lip, cleft palate, or cleft lip and palate patients; and orthognathic surgery patients. The study sample consisted of 83 consecutive patients undergoing treatment at the orthodontic unit of Christchurch Hospital, Christchurch, New Zealand, divided into 3 groups: 30 adolescents with severe malocclusions; 24 adolescents with cleft lip, cleft palate, or cleft lip and palate; and 29 adults with severe skeletal discrepancies requiring both orthognathic surgery and orthodontic treatment. Each patient completed the Short Form of the Oral Health Impact Profile (OHIP-14) questionnaire before and after orthodontic treatment. The baseline OHIP-14 subscale scores among the 3 study groups were significantly different, with the surgery patients having nearly twice the OHIP-14 scores of the other 2 groups for nearly half of the items (P <0.05). The surgery patients experienced the greatest reduction in OHIP-14 scores (ie, improvement in OHRQoL), with the largest effect sizes reported for the psychological discomfort (+2.73) and disability (+2.65) domains. The group with clefts experienced the smallest changes in OHIP-14 scores across all 7 domains (-0.03 to +0.63). After adjusting for age and sex, the surgical patients had a significantly greater reduction in pretreatment OHIP-14 scores than did the standard and the cleft patients (P <0.01). The effect of orthodontic treatment on OHRQoL varies for different patient groups even after adjusting for age and sex. The greatest improvement in OHRQoL occurred in adults with a need for orthognathic surgery, whereas the least improvement seemed to occur in adolescents with cleft lip, cleft palate, or cleft lip and palate.