Study objective We compare the analgesic effectiveness of intranasal fentanyl and ketamine in children. Methods This was a double-blind, randomized, controlled trial comparing fentanyl at 1.5 ?g/kg with ketamine at 1 mg/kg in children aged 3 to 13 years and weighing less than 50 kg, with isolated limb injury and pain of more than 6 of 10 at triage. The sample size was 40 in each arm. Subjects were coadministered oral ibuprofen at 10 mg/kg. The primary outcome was median pain rating reduction at 30 minutes. Secondary outcomes were pain rating reduction at 15 and 60 minutes, subjective improvement and satisfaction, University of Michigan Sedation Score, adverse events, and rescue analgesia. Results Eighty children enrolled, and 73 were available for analysis: 37 fentanyl and 36 ketamine. Median age was 8 years; 63 were male children; median baseline pain rating was 80 mm. At 30 minutes, median reductions for ketamine and fentanyl were 45 and 40 mm, respectively (difference 5 mm; 95 confidence interval [CI] -10 to 20 mm). Reductions exceeded 20 mm for ketamine and fentanyl in 82 and 79 of patients, respectively (difference 3 ; 95 CI -22 to 16 ). Pain rating reduction was maintained to 60 minutes in both groups. Satisfaction was reported for ketamine and fentanyl by 83 and 72 of patients, respectively (difference 11 ; 95 CI -9 to 30 ). Adverse events, mainly mild, were reported for ketamine and fentanyl by 78 and 40 of patients, respectively (difference 38 ; 95 CI -58 to 16 ). Three ketamine patients had a moderate degree of sedation by University of Michigan Sedation Score. Conclusion Intranasal fentanyl and ketamine were associated with similar pain reduction in children with moderate to severe pain from limb injury. Ketamine was associated with more minor adverse events. ? 2014 American College of Emergency Physicians.