Disseminated superficial actinic porokeratosis (DSAP) is an inherited dermatosis triggered by chronic ultraviolet light exposure. Cosmetic improvement has been noted with topical therapies or laser treatment. Lesions of DSAP are precancerous, having been reported to develop into squamous cell carcinomas (SCCs) or basal cell carcinomas (BCCs) occasionally. We describe a patient with longstanding DSAP who developed a primary CNS lymphoma. Palifermin (a keratinocyte growth factor analogue) was used as an adjuvant for his chemotherapy to minimize mucositis. Our patient noted marked clinical improvement of his DSAP following his chemotherapy for lymphoma. Follow-up has shown a sustained improvement of his DSAP with no development of any SCCs. Palifermin may be safe for use in individuals at high risk of developing SCCs and further research into keratinocyte growth factors and risk of development of SCC is warranted. Systemic chemotherapy appears to improve DSAP lesions.