Liquid nitrogen cryotherapy is an effective treatment modality for verrucae in children. However, sometimes the pain of the procedure is too much for the young child. In such instances the availability of an effective topical anesthetic would be of tremendous benefit. Warts are usually present on hardened skin, that is, the palms, periungual areas, and soles. In a double-blind, randomized, placebo-controlled, single-center, parallel-group trial with one visit, children (6-18 years old) and adults (>18 years old) had 2.5 g of lidocaine/prilocaine cream 5% applied under an occlusive dressing to the wart and a 1 to 2 mm area surrounding it 1 hour prior to liquid nitrogen cryotherapy. In both age groups the warts were subdivided by location-hardened skin areas versus nonhardened skin sites. The topical anesthetic was then removed and cryotherapy applied for 5 to 10 seconds. The pain of cryotherapy was assessed by the patient on a visual analogue scale (VAS) immediately after the cryotherapy and 4 and 8 hours later. There was no statistically significant difference in the pain of cryotherapy experienced following the application of active cream (n = 64) and placebo (n = 64). Exploratory subgroup analysis by wart location showed promising results for lidocaine/prilocaine cream 5% over placebo in children with warts on hardened skin sites (palms and soles). The topical anesthetic was safe and generally well-tolerated. Lidocaine/prilocaine cream 5% may provide some anesthesia in children receiving cryotherapy when the wart is on the palms or soles. Further studies are needed to better understand the site and age specificity of the anesthetic properties of lidocaine/prilocaine cream 5% when used to reduce the pain experienced during cryotherapy of warts.