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Objective: The objective was to determine whether the use of fentanyl with ketamine for emergency department (ED) rapid sequence intubation (RSI) results in fewer patients with systolic blood pressure (SBP) measurements outside the pre‐specified target range of 100–150 mm Hg following the induction of anesthesia. Methods This study was conducted in the ED of five Australian hospitals. A total of 290 participants were randomized to receive either fentanyl or 0.9% saline (placebo) in combination with ketamine and rocuronium, according to a weight‐based dosing schedule. The primary outcome was the proportion of patients in each group with at least one SBP measurement outside the prespecified range of 100–150 mm Hg (with adjustment for baseline abnormality). Secondary outcomes included first‐pass intubation success, hypotension, hypertension and hypoxia, mortality, and ventilator‐free days 30 days following enrollment. Results: A total of 142 in the fentanyl group and 148 in the placebo group commenced the protocol. A total of 66% of patients receiving fentanyl and 65% of patients receiving placebo met the primary outcome (difference = 1%, 95% CI = −10 to 12). Hypotension (SBP ≤ 99 mm Hg) was more common with fentanyl (29% vs. 16%; difference = 13%, 95% CI = 3% to 23%), while hypertension (≥150 mm Hg) occurred more with placebo (69% vs. 55%; difference = 14%, 95% CI = 3 to 24). First‐pass success rate, 30 day mortality, and ventilator‐free days were similar. Conclusions and Relevance: There was no difference in the primary outcome between groups, although lower blood pressures were more common with fentanyl. Clinicians should consider baseline hemodynamics and postinduction targets when deciding whether to use fentanyl as a coinduction agent with ketamine. [ABSTRACT FROM AUTHOR]