Segmental mandibulectomy (SM) is a morbid procedure, often indicated in the treatment of oral cavity pathology; however, the effect on quality of life resulting from resection of specific mandibular subsites has not previously been investigated. This study's primary aim was to evaluate differences in Health-Related Quality of Life (HRQoL) among patients who underwent segmental mandibulectomy with condylectomy (SMc+) or not (SMc-), and secondarily among patients who underwent SM with symphyseal resection (SMs+) or not (SMs-). A single-centre cross-sectional study was performed, identifying adults who had undergone SM over a 5-year period. Patients who had disease recurrence, further major head and neck surgery, or any surgery 3months prior to participating were excluded. Demographic, disease and treatment data were obtained via chart review. Participants completed the European Organisation for Treatment of Cancer 'General' and 'Head and Neck Specific' HRQoL modules. Condylectomy and midline-crossing resection were the primary and secondary predictor variables, while the primary outcome was HRQoL. Study variables were cross tabulated against predictor and outcome variables to identify potential confounders. The association between condylectomy and symphyseal resection on HRQoL was modelled using linear regression and subsequently with identified confounding factors. Forty-five enrolled participants completed questionnaires, of which 20 had undergone condylectomy and 14 symphyseal resection. Participants were majority male (68.9%) and on average 60.2±18years old, having undergone surgery 3.8±1.8years prior to participation. Prior to adjustment, Condylectomy patients reported significantly worse 'Emotional Function' (mean±standard deviation) (47.7±25.5 vs 68.4±26.6, P=.02), 'Social Function' (46.3±33.6 vs 61.4±28.9, P=.04) and 'Mouth Opening' (61.1±36.7 vs 29.8±38.3, P=.04) compared to the SMC- group. SMs+patients reported significantly worse scores in 'Social Function' (43.9±30.1 vs 48.3±32,1, P=.03), 'Dry Saliva' (65.1±35.3 vs 38.5±33.9, P<.01) and 'Social Eating' (48.5±45.6 vs 30.8±36.4, P<.01) compared to the SMs-group. Following adjustment only 'emotional function' in the SMc comparison retained significance (P=.04). SM causes anatomical distortion resulting in functional deficit. While the condyle and symphysis are theoretically functionally important, our findings suggest that morbidity associated with their resection may be the result of associated surgical and adjuvant treatment burden.