A 63-year-old man showed multiple concentric erythemato-nodular lesions of approximately 1.5–3 cm in diameter, located in the parietal and temporal region. The skin biopsy allowed histological diagnosis of infundibular epidermal cyst associated with chronic granulomatous flogosis; in one of these, a well-differentiated squamous cell carcinoma arising from the cyst wall was found. The patient received isotretinoin at the daily dosage of 0.5 mg/kg/day for 5 months. During 1-year follow-up, laboratory tests, computed tomography scans, and control histology were all in the normal range, with a good improvement of the lesions. Epidermal cysts and squamous cell carcinoma are both commonly encountered in practice. However, the association of epidermal inclusion cysts and squamous cell carcinoma in the skin is very rare. In some cases, including the present one, more potent chemopreventive strategies, such as the use of systemic retinoids, must be considered. Systemic retinoids are the most heavily researched chemopreventive agents and have shown promise for multiple types of cancer, including bladder and head and neck carcinomas. We would like to recommend the possibility to administer retinoids in a squamous cell carcinoma, achieving very satisfactory results; in our case, a complete remission of malignant lesion and an improvement of epidermal cysts were made, without the development of side effects associated with retinoids.