Background: Several studies have demonstrated that postoperative analgesia with either epidural (EPID) or intravenous (iv) fentanyl are clinically equivalent. However, the contribution of plasma fentanyl levels on the intensity of analgesia in patients receiving EPID fentanyl is not clear. Thus, the objective of this study was to determine if postoperative EPID analgesia with fentanyl was related to plasma fentanyl levels. Methods: Fourteen patients who underwent radical prostatectomies under balanced general anaesthesia were studied. All patients had a low thoracic EPID catheter placed before the induction of general anaesthesia. Upon arrival in the PACU, patients were randomised to receive a fentanyl bolus of 0.5–1.5 μg.kg−1 followed by a continuous infusion of 1 μg kg−1 hr−1 in either the EPID or iv routes via a PCA pump in a double-blind fashion. Bolus doses of 10 μg every 15 minutes with a one hourly maximum dose of 140 μg were provided. Infusions were stopped after 24 hours. Fentanyl plasma levels, rest and dynamic pain scores were then assessed at 30 minute intervals until rest pain scores were ≥7/10 (breakthrough time). Results: Patients were demographically similar. All patients experienced effective analgesia during the first 24 hours of infusion. There were no significant differences in plasma fentanyl levels of patients receiving either EPID or iv fentanyl (mean 1.46 vs 1.28) during the first eight interval measurements (0–210 min, p= 0.98) for all comparisons. However, median breakthrough pain occurred significantly earlier in the EPID group than in the iv group (120 vs 300 min, p= 0.02). Conclusions: Plasma levels of fentanyl were always above minimum effective analgesic concentrations (MEAC). These findings suggest that it may not be clinically possible to limit EPID fentanyl doses to those associated with spinal analgesia. Thus, supraspinal effects will always be present. Moreover, despite having similar fentanyl plasma levels, patients receiving EPID fentanyl had a shorter duration of analgesia than those in the iv group. These results suggest that patients receiving EPID fentanyl may develop acute tolerance to fentanyl therapy.