Background: Analgesics such as opioids are commonly used for pain control in emergency departments. correlated respiratory side effects and central nervous system depression confine opioids application as analgesic medication. New pain control choices such as Nitric oxide and Ketamine may be alternatives. This study evaluates efficacy of Nitric Oxide versus Ketamine in purpose of pain reduction in limbs fractures. Methods: In a randomized clinical study, 75 patients that were referred to the emergency department with pain, which has been caused by bone fractures, were randomly assigned into 2 groups: receiving ketamine with an intravenous bolus dose of 0.3 mg/kg versus mixture of 50% nitrous oxide/50% Oxygen. The pain score in the groups were measured and compared by the Visual Analog Scale consecutively at arrival and 5, 10, 15 minutes after intervention. Results: Fifteen minutes after the intervention, the score of pain in patients receiving ketamine, reached 2.5 from 8.86 at the baseline. This is while in the second group, 15 minutes after the treatment, reached to 5.02 from 9.52 at the baseline. The amount of pain reduction in both groups was statistically significant. A point-by-point comparison of the amount of the pain did not show significant differences in both groups. Conclusions: The findings of this study showed that both ketamine and Nitrous Oxide/Oxygen mixture are effective in alleviating the pain of patients with limb's fracture, however, there is no precedence between these medications as a pain killer.