The termeruptive squamous atypia(ESA) is used to describe squamous proliferations that do not present with high-grade histologic features and for which surgical management may exacerbate the condition. Non-surgical management of ESA with radiation, local or systemic chemotherapy, retinoids, or immunotherapy have been reported with variable success. In contrast, combination treatment with retinoids, immunomodulatory or chemotherapeutic agents may result in a more durable response. We report a case of recalcitrantESAof the lower extremities where complete clinical remission was induced with triple combination medical management with intralesional 5-fluorouracil, field treatment with topical 5-fluorouracil and imiquimod, and oral acitretin. Our case adds to the literature supporting combination medical therapy for challenging cases of ESA.