This prospective study compared the effectiveness of 1% diphenhydramine with 1% lidocaine for local anesthesia in repair of minor skin lacerations in adults with simple linear lacerations treated at our Emergency Department. Wounds were anesthetized with either lidocaine or diphenhydramine according to a random numbers table. Ninety-nine patients were included in the final analysis (51 received lidocaine; 48 diphenhydramine). Patients and physicians rated the pain of injection and suturing using a standard visual analog scale. Univariate and multivariate linear models were used on rank transformed scores of the patient and physician ratings of injection and suturing with p < 0.05 considered statistically significant. According to patient rating lidocaine was less painful for injection than diphenhydramine, with a statistically significant difference between the two anesthetics (p = 0.0017). There was no statistically significant difference in pain rating by physicians between the two anesthetics (p > 0.05). Pain with suturing was rated as minimal for both lidocaine and diphenhydramine with no statistically significant difference in the effectiveness according to either patients or physicians (p > 0.05). Lidocaine injection appears to hurt less than diphenhydramine injection according to the patients. Pain of suturing corresponding to anesthetic effectiveness appears to be equivalent for lidocaine and diphenhydramine according to both physicians and patients. Although diphenhydramine should not be substituted for lidocaine, it appears to be a viable alternative in the management of patients with allergy to amides or extremely large lacerations in which a maximum of amide anesthetic has been used.