Purpose <p>The aim of this study was to assess whether norepinephrine at the time of extubation increases reintubation rates in critically ill patients with obesity.</p> Methods <p>The initial step was to analyze data that had been collected prospectively, using a retrospective approach—defined as the main cohort. Then, we validated our findings using data from a multicenter randomized-controlled trial (validation cohort). The primary objective was to compare reintubation within 7&#xa0;days, between patients with norepinephrine and without norepinephrine at the time of extubation. The secondary objective was to assess norepinephrine doses at extubation, normalized to body weight.</p> Results <p>Among the 3186 patients included in the main cohort, 837 had obesity. Among them, 213 (25%) were extubated with norepinephrine, with a median norepinephrine dose at extubation of 0.6&#xa0;mg/h of absolute value which corresponds to 0.097 (0.04–0.17) µg/kg/min of real body weight. No significant difference in reintubation rates was observed between patients extubated with norepinephrine (16%) and those without (17%, <i>p</i> = 0.85). Among the 656 patients with obesity in the validation cohort, we observed similar results, with a reintubation rate of 18% in those extubated with norepinephrine and 15% in those without (<i>p</i> = 0.45). Similar results were observed in the 2349 patients without obesity.</p> Interpretation <p>In critically ill patients with obesity, the use of norepinephrine at the time of extubation did not significantly increase the reintubation rates.</p> Clinical trial registration <p>NCT04014920 for the validation cohort.</p>