To determine whether ketamine use for tracheal intubation, compared to other sedative use, is associated with a lower risk of post-intubation hypotension in hemodynamically-unstable patients in the emergency department (ED), we analyzed the data of a prospective, multicenter, observational study-the second Japanese Emergency Airway Network (JEAN-2) Study-from February 2012 through November 2017. The current analysis included adult non-cardiac-arrest ED patients with a pre-intubation shock index of ≥0.9. The primary exposure was ketamine use as a sedative for intubation, with midazolam or propofol use as the reference. The primary outcome was post-intubation hypotension. A total of 977 patients was included in the current analysis. Overall, 24% of patients developed post-intubation hypotension. The ketamine group had a lower risk of post-intubation hypotension compared to the reference group (15% vs 29%, unadjusted odds ratio [OR] 0.45 [95% CI 0.31-0.66] p < 0.001). This association remained significant in the multivariable analysis (adjusted OR 0.43 [95% CI 0.28-0.64] p < 0.001). Likewise, in the propensity-score matching analysis, the patients with ketamine use also had a significantly lower risk of post-intubation hypotension (OR 0.47 [95% CI, 0.31-0.71] P < 0.001). Our observations support ketamine use as a safe sedative agent for intubation in hemodynamically-unstable patients in the ED.