Background: Pierre Robin Sequence (PRS) presents in isolation [iPRS] or in conjunction with a genetic syndrome [sPRS] that can subsequently lead to respiratory dysfunction and eventual failure to thrive. Mandibular distraction osteogenesis (MDO) has gained popularity as a way to surgically address the airway obstruction in PRS. sPRS patients routinely have a more challenging clinical course, and there is a paucity of data comparing the effectiveness of MDO as a treatment for sPRS versus iPRS. That said, this study analyzed MDO in both sPRS and iPRS patients within a relatively large single institution cohort. Methods: A retrospective review was conducted on all PRS patients who underwent MDO by a single surgeon between 2015 and 2022. The patients were stratified into iPRS or sPRS based on genetic evaluation (N = 50). Primary measures were demographic and situational data; outcome measures included tracheostomy and gastrostomy tube (g-tube) avoidance, Apnea-Hypoxia Index (AHI), and laryngeal view predistraction and at time of distractor removal. Results: Prior to distraction, iPRS (N = 32) and sPRS (N = 18) patients showed no significant differences in age (105.1 ± 199.7 days; range 2-1051 days), AHI (17.3 ± 17.1; range 3.6-90), or laryngeal view (65% grade III or IV) ( P > .05). Overall, post-MDO, there was a statistically significant decrease in mean AHI 17.3 to 4.5 ( P < .001). sPRS patients in particular had a significant decrease in average AHI following MDO from 15.2 to 4.5 ( P = .028). Post-MDO both groups had similar improvement of laryngeal view, and avoidance of g-tube ( P < .05). Conclusions: MDO was found to be an effective technique to improve airway obstruction in both sPRS and iPRS. Despite the fact that sPRS patients typically have a more challenging clinical course, an equivalent clinical improvement in airway outcomes was seen between sPRS and iPRS patients post-MDO.