Orthognathic surgery (OGS) has been successfully adopted for managing a wide spectrum of skeletofacial deformities, but patients with underlying conditions have not been treated using OGS because of the relatively high risk of surgical anesthetic procedure-related complications. This study compared the OGS outcomes of patients with and without underlying high-risk conditions, which were managed using a comprehensive, multidisciplinary team-based OGS approach with condition-specific practical perioperative care guidelines. Data of surgical anesthetic outcomes (intraoperative blood loss, operative duration, need for prolonged intubation, reintubation, admission to an intensive care unit, length of hospital stay, and complications), facial esthetic outcomes (professional panel assessment), and patient-reported outcomes (FACE-Q social function, psychological well-being, and satisfaction with decision scales) of consecutive patients with underlying high-risk conditions (n = 30) treated between 2004 and 2017 were retrospectively collected. Patients without these underlying conditions (n = 30) treated during the same period were randomly selected for comparison. FACE-Q reports of 50 ethnicity-, sex-, and age-matched healthy individuals were obtained. The OGS-treated patients with and without underlying high-risk conditions differed significantly in their American Society of Anesthesiologists Physical Status (ASA-PS) classification (p < 0.05), Charlson comorbidity scores, and Elixhauser comorbidity scores. The two groups presented similar outcomes (all p > 0.05) for all assessed outcome parameters, except for intraoperative blood loss (p < 0.001; 974.3 ± 592.7 mL vs. 657.6 ± 355.0 mL). Comparisons with healthy individuals revealed no significant differences (p > 0.05). The patients with underlying high-risk conditions treated using a multidisciplinary team-based OGS approach and the patients without the conditions had similar OGS-related outcomes.