OBJECTIVE Intramuscular injections may be painful. Some of this pain may be caused by the infiltration of medication into the muscle, separate from the pain of skin puncture. We hypothesized that topical application of lidocaine/prilocaine (EMLA) cream would reduce the pain of intramuscular infiltration. METHODS A double-blinded, placebo-controlled study was performed in 40 adult volunteers to compare the pain of needle puncture and of infiltration of saline into the deltoid muscle after application of EMLA cream or placebo. Each subject served as his or her own control. Pain scores were obtained by using a 100 mm visual analog scale (VAS). RESULTS Pain associated with needle puncture was significantly reduced by EMLA cream as compared with placebo (median VAS score, 7.5 vs 19.5; p = 0.0043), as was pain associated with intramuscular infiltration (median VAS score, 2.5 vs 11; p < 0.00005). CONCLUSIONS Our results suggest that further clinical studies of EMLA cream for modifying perceived pain from intramuscular injection in children are warranted.