Statement of the Problem: While there are numerous therapeutic options available for intransit cutaneous melanoma, the treatments are often unsuccessful due to suboptimal response rates. This motivates the use of combination therapies such as imiquimod and 5- fluorouracil to increase therapeutic efficacy. Imiquimod and 5- fluorouracil have distinct mechanisms of action, with imiquimod binding to toll-like receptor 7 and 8 on leukocytes and 5-FU inhibiting thymidylate synthase and inhibiting DNA synthesis. The purpose of this case report is to describe the course of an 87-year-old female with an 8-year history of cutaneous melanoma. Findings: The patient was initially managed with a wide local excision of the right shin lesion, as well as a split-thickness graft. She was further treated with a combination of 5% topical imiquimod cream and 5% 5-fluorouracil cream. There was complete clearance within 23 months, and the patient has been disease-free since. Conclusion & Significance: Given the patient’s complete clearance and disease-free state since treatment, we postulate that imiquimod and 5-FU’s synergistic mechanisms of action provide a valuable potential for targeting in-transit cutaneous melanoma in patients.