Objective: To compare the analgesiceffects of Nitrous oxide and morphine sulfate in patients with acute renalcolic due to urolithiasis.Methods: This  was randomized clinical trial being performed in Imam Hossein hospital affiliated with Shahid Beheshti University  of Medical Sciences during a 1-year period from May2013 to May2014.  A  total of number of 100 patients, with an age range of 20-50 years, who presented with renal colic secondary to urolithiasis confirmed by ultrasonography were randomly assigned to receive morphine sulfate injection (0.1 mg/kg)  with100 mg diclofenac suppository (n=50) or Entonox exhalation (50% nitric oxide and 50% oxygen)for 30-minutes with 100 mg diclofenac suppository (n=50). Quantitative measurement was of pain was performed according to a visual  analogue scale (VAS), before, 3, 5, 10 and 30-minute after the intervention. The pain severity and side effects were measured between two study groups.Results: The baseline characteristics of the patients in two study groups were comparable. The frequencies of pain persistence (at least 50%) at 3-, 5-, 10- and 30-minute intervals in morphine sulfategroup were 96%, 80%,50% and 8%, respectively; these frequencies in Entonex were 82%, 42%, 12% and 2%, respectively (p<0.001). Cox regression modeling showed that use of Entonox was the only effective agent in the success of treatment, compared to the use of morphine, i.e. use of Entonox increased the success of treatment up to 2.1 folds compared to the use of morphine (HR=2.1; 95% CI: 1.2-3.6; p=0.006).Conclusion: The results of the present study demonstrate that inhalation of Entonox is an effective and safe analgesic regimen for acute renal colic. It acts more rapidly and is more potent in relieving renal colic when compared to morphine sulfate.Entonox can be regarded as an appropriate alternative to analgesics like opioids in this ground.Clinical Trial Registry: The current study is registered with Iranian Registry for Clinical Trials (www.irct.ir; IRCT2014120215620N4)