Postoperative nausea and vomiting comprise significant morbidity in pediatric patients undergoing strabismus repair and can prolong hospitalization. Many authors recommend routine intraoperative opiate analgesia and prophylactic antiemetics. A prospective, comparative, randomized study to assess rectal acetaminophen (n = 45) to intravenous fentanyl-droperidol (n = 45) to resolve recovery profile, emesis rate, and adequacy of analgesia in a pediatric strabismus repair population was performed, with standardization of the anesthetic technique. Data on pharmacoeconomic cost-effectiveness analysis, willingness to pay, and willingness to repeat were elucidated. Emesis rate in the acetaminophen group was 9%, and the fentanyl-droperidol group was 13% (not statistically significant). There was a statistically significant shorter wake-up time, time in postanesthesia recovery, time in ambulatory surgery unit, time to first verbal command, time to first oral intake, time to ambulation, and time to return to normal activity in the acetaminophen group (P < 0.05). Postoperative analgesic potency of rectal acetaminophen was adequate and equivalent by Observer Pain Scale. Parental satisfaction was similar by willingness-to-pay and willingness-to-repeat postoperative survey. Cost-effectiveness ratio (i.e., cost per treatment success) for acetaminophen and fentanyl-droperidol groups was $0.33 and $87.91, respectively. Prophylactic fentanyl-droperidol prolongs the length-to-stay and recovery time and provides no discrete identifiable benefit over acetaminophen alone in this population. Cost-effectiveness analysis strongly favors use of acetaminophen over fentanyl-droperidol prophylaxis in children undergoing primary strabismus surgery.