Importance: Supraglottoplasty (SGP) failure is frequently attributed to coexistent medical comorbidities, but studies specifically evaluating outcomes in these populations are lacking., Objective: To assess SGP outcomes in patients with neurologic and syndromic comorbidities and severe laryngomalacia (LM)., Design, Setting, and Participants: Case series with retrospective review of medical records of 54 patients with neurologic and/or syndromic comorbidity and severe LM who underwent SGP between 2004 and 2012 at a tertiary care pediatric institution., Interventions: Patients presented with severe LM that required SGP. Supraglottoplasty failure necessitated revision SGP, tracheostomy, or gastrostomy tube insertion, or LM and obstructive sleep apnea that required assisted ventilation (continuous positive airway pressure and bilevel positive airway pressure)., Main Outcomes and Measures: Medical records were reviewed with a focus on patient factors, surgical timing, complications, and surgical and dysphagia outcomes. Patients were grouped based on their age at the time of SGP as infants (aged ≤12 months) and children (aged >12 months). Statistical comparisons were performed with SGP outcomes of infants with LM and no comorbidities., Results: Fifty-four patients met the inclusion criteria. Thirty-one (13 infants, 18 children) had a neurologic condition and 23 (15 infants, 8 children) had syndromes. The overall success rate of SGP was 67% (36 of 54) in these populations. Neurologic (P = .003) and syndromic (P < .001) comorbidities were associated with significant reduction in SGP success rates vs no comorbidities. Among SGP failures (18 of 54 [33%]), 13% (7 of 54) required tracheostomy, 9% (5 of 54) needed assisted ventilation, 7% (4 of 54) required a postoperative gastrostomy tube, and 4% (2 of 54) required revision SGP. In the neurologic comorbidities group, patients with cerebral palsy had significantly higher tracheostomy rates compared with those who had other neurologic pathologies constituting comorbidities (2 of 11 [18%] vs 0 of 20; P = .049). In infants, acute airway obstruction was the most common indication for SGP in the neurologically comorbidity and syndrome populations (success rates, 69% and 67%, respectively). In children, obstructive sleep apnea was the most common indication for SGP in the neurologic comorbidity and syndrome populations (success rates, 78% and 50%, respectively)., Conclusions and Relevance: Supraglottoplasty remains useful and outcomes were better in patients with neurologic comorbidity than in patients with syndromic comorbidity.