Background: Local anesthetic injections can be painful and distressing. Objective: The aim of this study was to determine whether nitrous oxide, ice, vibration, or topical anesthetic improves analgesia for local anesthetic injections. Method: A cohort study of 400 patients undergoing Mohs micrographic surgery with local anesthetic was conducted. Patients received no intervention (n = 200), ice (n = 50), topical anesthetic cream (n = 50), vibration device (n = 50), or nitrous oxide (n = 50). Pain was rated using the Visual Analogue Scale (VAS) and Wong-Baker FACES Pain Rating Scale. Results: Without intervention, mean VAS was 4.2 and FACES was 4.6. Nitrous oxide was the most successful in reducing pain (mean VAS 1.6 vs. 4.2, P < .01, FACES 1.2 vs. 4.6, P < .01). Topical ice reduced pain (mean VAS 3.0 vs. 4.2, P < .01, FACES 3.0 vs. 4.6, P < .01). Vibration reduced pain (mean VAS 3.5 vs. 4.2, P < .01, FACES 3.6 vs. 4.6, P < .01). Higher pain scores were associated with age <50 (P = .02), male sex (P = .05), and surgery on the nose, lip, ear, or eyelid (P = .02). Conclusion: Nitrous oxide, ice, and vibration reduce injection pain. These interventions are especially useful for younger males undergoing surgery on the nose, lip, ear, or eyelid.