OBJECTIVE: To investigate how craniofacial syndromes influence surgical outcomes of mandibular distraction osteogenesis (MDO), in order to optimize perioperative care. DESIGN: Retrospective cohort. SETTING: Single-center. PATIENTS/PARTICIPANTS: The American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-Pediatric) database was queried for relevant Current Procedural Terminology (CPT) codes from 2012 to 2022. Patients with craniofacial syndromes were identified using ICD-9 and ICD-10 codes. INTERVENTION: Mandibular distraction osteogenesis. MAIN OUTCOME MEASURES: 30-day perioperative adverse events including reoperation, readmission, and complications such as infection, dehiscence, pneumonia, sepsis, stroke, intracranial hemorrhage, nerve injury, and death. RESULTS: A total of 209 patients were identified, with 77 (36.8%) having a craniofacial syndrome. The average age at MDO was significantly younger for patients with craniofacial syndromes (99 days) versus the nonsyndromic group (389 days). Patients with craniofacial syndromes had a higher likelihood of undergoing reoperation within 30 days postoperatively ( CONCLUSIONS: This nationwide analysis indicates that while overall complication rates for MDO are similar, those with craniofacial syndromes face greater challenges, including higher reoperation rates, longer LOS, and lower same-day discharge rates, compared to patients without craniofacial syndromes. These results underscore the need for tailored postoperative care strategies to improve outcomes for this unique patient population.