ObjectiveThe aim of this cross-sectional study was to explore the relationship between quality of life (QoL) and body image distress in patients with head and neck cancer (HNC), considering relevant psychological variables (i.e., coping strategies, social anxiety symptoms, self-esteem, intolerance of uncertainty, pain, and distress). We also aimed to explore gender differences in patients with HNC in terms of relevant psychological variables in HNC.MethodsFifty-one HNC patients (37 males and 14 females) completed self-report questionnaires to assess body image distress, physical and mental QoL, and relevant psychological variables in HNC (coping strategies, social anxiety symptoms, self-esteem, intolerance of uncertainty, pain, and distress) before undergoing treatment. Pearson’s correlations and four-step hierarchical regressions were performed to assess the relationship between body image distress, QoL, and the abovementioned psychological variables, while one-way analyses of variance and one-way analysis of covariance were employed to assess gender differences.ResultsPhysical QoL was associated with body image distress above and beyond disease duration, distress, coping strategies, pain, mental QoL, and self-esteem, while mental QoL was associated with pain above and beyond distress, coping strategies, physical QoL, self-esteem, and body image distress. Concerning gender differences, females scored higher than males on most of the explored psychological variables, except for physical QoL and intolerance of uncertainty, and showed lower mental QoL and self-esteem than males.ConclusionBody image distress and pain emerged as negatively associated with QoL, and almost all the explored psychological variables differed among genders. Psychological interventions targeting body image distress and pain should be promoted in patients with HNC to increase their QoL, while keeping gender differences in mind.