In this double-blind study, we compared the efficacy of epidural versus IV administration of alfentanil in combination with small-dose bupivacaine for postoperative pain relief. Thirty-two patients were randomly allocated to one of two study groups. Patients from both groups received an epidural loading dose of 60 mg of bupivacaine (12 mL of 0.5%). Subsequently, patients in the epidural (EPI) group received an infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) plus alfentanil (0.36 mg/h) and an IV infusion (8 mL/h) of NaCl 0.9%. Patients in the IV group received an epidural infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) and an IV infusion (8 mL/h) of alfentanil (0.36 mg/h). Infusions were maintained for 24 h. These dose regimens were such that equivalent subanalgesic plasma concentrations of alfentanil were obtained. Patient-controlled analgesia with morphine was available to both groups. Time to onset of postoperative pain and morphine consumption were used as variables to compare the two regimens. Measured plasma concentrations of alfentanil during the postoperative observation period were similar (<20 ng/mL) in both groups. Median times to onset of postoperative pain (EPI 600 min, IV 360 min) and total morphine consumption (EPI 11 mg, IV 10 mg) did not differ between the groups (P > 0.2). We conclude that, in combination with epidural bupivacaine 0.125%, an IV infusion of alfentanil is equally effective as an epidural infusion of alfentanil if the plasma concentrations are the same. The study did not demonstrate a spinal mechanism of action for alfentanil. Implications: This randomized, double-blind study showed that, when combined with small-dose bupivacaine (0.125%), epidurally administered alfentanil is not more effective than IV administered alfentanil for postoperative pain management when the regimens are such that equivalent subanalgesic plasma alfentanil concentrations are obtained. A spinal mechanism of action for alfentanil could therefore not be demonstrated. (Anesth Analg 1998;86:574-8)