Hospitalized preterm infants undergo multiple painful heel lances. A two-phase, randomized, controlled trial was undertaken to determine the safety and efficacy of lidocaine-prilocaine 5% cream (EMLA, Astra Pharmaceuticals, L.P, Westborough, MA) for relieving pain from heel lance. One hundred twenty infants were randomly assigned to receive 0.5 g of EMLA or placebo cream for 30 minutes (Phase 1) or 60 minutes (Phase 2) before a routine heel lance. Efficacy was assessed using the Premature Infant Pain Profile (PIPP). Safety was determined by methemoglobin concentration 8 hours after EMLA application and by clinical signs of methemoglobinemia. No significant differences existed on PIPP scores between EMLA and placebo groups in Phase 1 (p < .480) or Phase 2 (p < .831). No infant had any clinical signs of methemoglobinemia. The mean methemoglobin concentration was 1.19% (.47). Approximately 10% of infants had minor skin reactions, and approximately 20% of EMLA-treated infants had blanching at the application site. The authors conclude that EMLA is safe but not efficacious for relieving pain from heel lance in preterm infants.