Background <p>Following greater than or equal to 48-h intubation, one-third of acute respiratory failure (ARF) patients aspirate. Laryngeal edema has been identified as a potentially modifiable risk factor of post-extubation aspiration. The aim of this case–control study was to characterize the anatomical distribution of post-extubation laryngeal edema and to correlate anatomical laryngeal edema severity with aspiration risk in ARF survivors. The study also assessed whether patient weakness influenced the relationship between laryngeal edema and aspiration risk.</p> Methods <p>Flexible endoscopic evaluation of swallowing (FEES) videos from 120 patients (60 aspirators, 60 non-aspirators) were obtained from a previous multicenter observational study. Laryngeal edema was rated in eight locations using the Revised Patterson Edema Scale (RPES). Aspiration status was determined by a clinical rater core, and patient weakness was assessed using peak cough flow and pharyngeal medialization outcomes. Bivariate associations with aspiration were tested using Fisher’s exact tests. Logistic regression models were used to test for associations between anatomical laryngeal edema severity and risk of aspiration. Logistic regression models were fit to explore whether weakness modified the relationship between edema and aspiration risk.</p> Results <p>The strongest anatomic predictor of post-extubation aspiration was the presence of aryepiglottic fold edema (adjusted odds ratio, aOR = 5.74, <i>p</i> = 0.009, FDR-adjusted <i>p</i> = 0.073). Weakness independently increased aspiration risk [aOR = 3.93 (95%CI = 1.42, 11.9), <i>p</i> = 0.011], but without evidence of an interaction effect with edema (<i>p</i> = 0.15).</p> Conclusion <p>These findings can inform future research studying the influence of laryngeal edema on aspiration risk, as well as interventional studies aimed at reducing adverse outcomes associated with laryngeal edema.</p>