The aim of this study was to examine the pathways between temporomandibular disorders (TMDs), occlusal characteristics, facial pain, and oral health-related quality of life in patients with severe malocclusion. The study comprised 94 (34 men and 60 women, mean age 38 years) adult patients who were referred for orthodontic or surgical-orthodontic treatment. All the patients had severe malocclusion. Oral health-related quality of life was measured with the Oral Health Impact Profile-14 scale (OHIP-14), the intensity of facial pain using a Visual Analogue Scale (VAS), TMD with Helkimo's clinical dysfunction index (Di), and occlusal characteristics with the Peer Assessment Rating (PAR). A hypothetical model of the interrelationships between these factors was constructed based on the conceptual model of biological, behavioural, and psychosocial consequences of oral diseases. The associations were studied with path analysis. Women reported poorer oral health-related quality of life, higher pain levels, and had more severe TMD than men, but the gender difference was statistically significant only in pain and TMD. In contrast to the hypothetical model, among women the occlusal characteristics were not directly associated with oral health-related quality of life or facial pain. Among men, the occlusal characteristics were directly associated with oral health-related quality of life. In conclusion, patients with severe malocclusion who also have TMD and facial pain more often have impaired oral health-related quality of life. The associations of the occlusal characteristics with oral health-related quality of life differ between genders. Therefore, these associations should be studied separately among genders.