Depilatory creams are widely used in research to remove hair in preparation for surgery, imaging, and other procedures. However, few studies have evaluated the effects of these creams on mouse skin. We sought to determine the cutaneous effects of 2 different depilatory formulations of a widely used brand as related to the duration of exposure. We compared a standard body formula [BF] and a facial formula [FF] that is marketed as being more gentle on skin. The cream was applied to one flank for 15, 30, 60, or 120 s; hair on the contralateral flank was clipped and used as a control. Treatment and control skin were scored for gross lesions (erythema, ulceration, and edema), degree of depilation, and histopathologic changes. C57BL/6J (B6) and Crl:CD-1(ICR) (CD-1) mice were used to allow comparison of an inbred/pigmented strain to an outbred/albino strain. BF caused significant cutaneous injury to both strains of mice, whereas FF produced significant cutaneous injury only in CD-1 mice. Both strains showed gross skin erythema, with the most severe erythema seen in CD-1 mice treated with BF. Contact time did not affect histopathologic changes or gross erythema. Both formulations produced depilation comparable to clipping in both strains when left on for a sufficient duration. In CD-1, mice, BF required at least 15 s of exposure, whereas FF required at least 120 s. In B6 mice, BF required at least 30 s of exposure, whereas FF required at least 120 s. The 2 mouse strains did not show statistically significant differences in erythema or histopathologic lesions. Overall, these depilatory creams were comparable to clippers for hair removal from mice but they produce cutaneous injury that may affect research outcomes.