Cutaneous T-cell lymphoma (CTCL) is a chronic form of skin cancer. Skin-directed therapies rarely achieve complete clearance of lesions, and recurrences are frequent. In this case series, 9 patients with stage IA to IVA2 CTCL received intralesional (IL) therapy with 5-fluorouracil (5-FU) and imiquimod (IMQ) cream 5% daily to recalcitrant plaques and tumors. All 9 patients attained a complete response (CR) with no recurrences reported and no severe side effects. We find that combination IL 5-FU and IMQ cream 5% daily is a well-tolerated, effective, and durable skin-directed therapy for recalcitrant plaques and tumors in CTCL.