Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer in the United States.1,2 There are different treatment modalities for non-melanoma skin cancer, that include surgical excision, radiation therapy, cryotherapy, electrodessication and curettage, photodynamic therapy, and topical chemotherapy. Intralesional injection with 5-fluorouracil is a treatment modality that is not used often, perhaps due to not much research available to its effectiveness or established treatment recommendations. We report a case of a patient with multiple lesions of cutaneous squamous cell carcinoma on the lower extremities treated successfully with intralesional 5- fluorouracil.