Objective: We compared the prognosis of patients with erythrodermic mycosis fungoides (MF) administered total skin electron beam radiation (TSEB) plus neoadjuvant, concurrent, and adjuvant extracorporeal photopheresis (ECP) with the prognosis of patients administered only TSEB. Outcomes of clinical interest include disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and cause-specific survival (CSS). Methods: This study was a retrospective nonrandomized series. Between 1974 and 1997, a total of 44 patients with erythrodermic MF from the Department of Therapeutic Radiology, Yale University School of Medicine, and the Department of Radiation Oncology, Cancer Care Ontario, Hamilton, Ontario, were collected and analyzed as a group (Hamilton = 15, Yale = 29). These patients received TSEB consisting of 32 to 40 Gy via 4 to 6 MeV. Twenty-one patients at Yale also received ECP treatment 2 days per month for a median of 6 months. Median age was 68 years (range, 29-82 years) at the commencement of TSEB, and 66% were male. Seventy-three percent of patients had received other therapies before TSEB, including 75 courses that failed to control disease (n = 15 systemic therapy, 16 biologicals, and 44 topical therapies). At TSEB, 59% had hematologic involvement (B1), 30% were stage IVA (N3), and 13% were IVB (M1). Median follow-up was 2.2 years (range, 0.3-13.9 years) subsequent to TSEB and 3.7 years from diagnosis (range, 0.8-16.8 years). Results: All patients responded to TSEB within 2 months of completion, with a cutaneous complete response rate of 73%. For the 32 complete responders the 3-year DFS was 63%. It was 49% for those 17 patients who received only TSEB compared with 81% for those 15 patients who received TSEB + ECP. Cox regression analysis demonstrated that ECP was associated with prolonged remission (DFS multivariate P = .024, adjusting for B1 and stage). The 2-year PFS, CSS, and OS for the TSEB group were 36%, 69%, and 63%, respectively, compared with 66%, 100%, and 88% for the TSEB + ECP cohort. Cox regression demonstrated that ECP was associated with CSS (multivariate P = .048, adjusting for B1 and stage). For those who progressed, a total of 49 subsequent courses of therapy were administered (n = 20 chemotherapy, 10 biologicals, and 19 topical therapies). Thirteen patients died from MF-related causes, and 8 died from other causes. Acute and chronic toxicities were consistent with those previously reported. Conclusion: ECP given concurrently with, or immediately after, TSEB (32-40 Gy) significantly improves both PFS and CSS for patients with erythrodermic MF compared with TSEB without the addition of ECP. (J Am Acad Dermatol 2000;43:54-60.)