The response to treatment with four topical preparations was evaluated in an 11-year-old Morgan horse mare with histologically confirmed quadrilateral cannon hyperkeratosis. Each limb was treated for 30 days with 0.1% tacrolimus ointment, 0.1% adapalene gel, 0.2% phytosphingosine spray or a water-based emollient. Response to treatment was evaluated both histologically and visually. A water-based emollient and 0.1% tacrolimus ointment produced encouraging clinical responses. Pre-treatment histopathology identified marked, mostly compact, hyperkeratosis and follicular hyperkeratosis, most prominent in the infundibular area. Following treatment, histopathology identified a mild reduction in follicular keratin production and stratum corneum thickness.