Study objective We compare the analgesic efficacy of topical anesthetics for dermal instrumentation with conventional infiltrated local anesthesia and also compare topically available amide and ester agents with a eutectic mixture of local anesthetics (EMLA). Methods We conducted a systematic review of randomized, controlled trials. Relevant literature was identified through searches of MEDLINE, Cochrane Central Register of Controlled Trials, and the Excerpta Medica Database Drugs and Pharmacology. We limited the type of procedures to puncture of intact skin with a needle. The primary outcome was analgesic efficacy, reflected in the patient's self-report of pain intensity during dermal instrumentation. Where possible, quantitative methods were used to summarize the results. Results We identified 25 randomized controlled trials including 2,096 subjects. The results of the trials comparing the efficacy of EMLA with infiltrated local anesthetic were inconsistent. Qualitative analysis demonstrated comparable analgesic efficacy between liposome-encapsulated lidocaine and EMLA. The weighted mean difference in 100-mm visual analogue scale pain scores favored topical tetracaine over EMLA (−8.1 mm; 95% confidence interval −15.6 mm to −0.6 mm). Liposome-encapsulated tetracaine provided greater analgesia than EMLA according to the weighted mean difference in 100-mm visual analogue scale scores (−10.9 mm; 95% confidence interval −15.9 mm to −5.9 mm). Conclusion EMLA may be an effective, noninvasive means of analgesia before dermal procedures. However, we identified 3 topical anesthetics that are at least as efficacious as EMLA: tetracaine, liposome-encapsulated tetracaine, and liposome-encapsulated lidocaine. Liposomal lidocaine is commercially available in the United States and offers a more rapid onset and less expensive alternative to EMLA.