A 33-year-old man presented to our emergency department with vaso-occlusive crisis after few days of worsening shoulder, back, and hip pain refractory to oral opioids. He was admitted to the intensive care unit with severe painful sickle cell crisis with no response to high doses of IV morphine and adjuvant analgesics. A ketamine(10 mg bolus and 0.2 mg/kg/h infusion)-midazolam(2 mg bolus and 1mg/h infusion)regimen was administered along with the opioids, after which the patient felt comfortable for the first time since admission. Ketamine was discontinued on day 9 of hospitalization and the patient was discharged on day 12. He could transit to oral opioids compatible with discharge. Low dose ketamine midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis.