OBJECTIVE To determine the efficacy of topical anesthetic cream, eutectic mixture of local anesthetics (EMLA), in alleviating pain from neonatal circumcision. METHODS Randomized, controlled trial. METHODS Normal newborn nursery in a university teaching hospital. METHODS Twenty-seven newborn, full-term male neonates, aged 1 to 3 days. METHODS Heart rate, transcutaneous oxygen saturation, facial activity, and crying. RESULTS Compared with baseline, all newborns experienced pain as evidenced by increased heart rate of an average of 40 beats per minute (F [8, 25] = 14.12; P < .0001), decreased oxygen saturation of 3% (F [8, 25] = 15.02; P < .0001), and more facial actions indicative of pain (F [8, 25] = 5.25; P < .002) during all phases of the procedure. Compared with placebo, EMLA significantly attenuated the pain response as shown by lower heart rate of an average of 25 beats per minute (F [1, 25] = 14.92; P < .001), higher oxygen saturation of 5%, particularly during the clamping and lysis phases (F [1, 25] = 19.83; P < .0001), 20% less facial activity (F [1, 25] = 12.01; P < .002), and 15% less crying during the clamping, Gomco clamp application, and incision of the foreskin. There were no differences between groups in the spectral crying parameters. CONCLUSIONS Circumcision procedure produces pain responses that EMLA diminishes. Thus, EMLA may be a useful agent for pain management in neonatal circumcision.