Using a prospective, randomized, and double-blind study design, alfentanil (n = 15), fentanyl (n = 14), or sufentanil (n = 16), in combination with N2O, were administered to patients undergoing craniotomy for supratentorial tumor resection. Physicians were given two syringes, one of which was labeled as “load” for the initial loading dose and the other as “maintenance” for continuous infusion. The concentration of drug in each syringe was adjusted to permit administration on a milliliter per kilogram basis. The target loading doses for alfentanil, fentanyl, and sufentanil were 75, 10, and 1 μg/kg, respectively, and initial infusion rates were 33.5, 2.0, and 0.3 μg·kg−1·h−1, respectively. Additional supplementary boluses and changes in maintenance infusion rate were made according to predetermined guidelines. Isoflurane, in increasing 0.2% inspired increments, was used only when the maximum allowed opioid dose had been given (i.e., supplementary bolus doses equal to 75% of the calculated loading dose or supplementary bolus doses equal to 50% of the calculated loading dose combined with a 50% increase in the maintenance infusion rate). Opioid infusions were stopped at the time of bone flap replacement. Antihypertensive medications and naloxone were subsequently given at the discretion of the anesthesiologist. Group demographics were not different. Total volumes of drug were similar among groups indicating equipotent preparations. Administration of isoflurane, antihypertensive medications, and naloxone were not different among groups. Although decreases in blood pressure seen with induction were similar among groups, alfentanil-treated patients received ephedrine more frequently before intubation. Thirty minutes after entry into the postanesthesia recovery area, respiratory rate andpH were lowest in sufentanil-treated patients. Level of consciousness among groups in the postanesthesia recovery area was not significantly different, although there appeared to be a tendency for alfentanil-treated patients to be more alert. No other variables, including brain condition upon dural opening, durations of intubation following either discontinuance of the maintenance infusion or completion of the head dressings, duration of intensive monitoring following surgery, or final discharge neurologic status were found to distinguish one opioid as superior to the others. Pharmacy opioid acquisition cost per procedure was greatest for the alfentanil-treated group.