Background: Both interferon alfa and extracorporeal photochemotherapy have been shown to be effective in primary cutaneous T-cell lymphomas (CTCLs). However, no prospective trial has been published on the combination of both treatments, although retrospective investigations suggested a better efficacy than for either interferon or extracorporeal photochemotherapy. Objective: Our purpose was to evaluate the efficacy and toxicity of combined interferon alfa-2a with extracorporeal photochemotherapy in a prospective controlled trial. Methods: A prospective controlled study was performed. Fourteen patients (all male) aged 38 to 72 years with CTCL of the mycosis fungoides type, stage IIa/IIb, and a 72-year-old male patient with a Ki-1 lymphoma were treated twice a month for 6 months with extracorporeal photochemotherapy using oral 8-methoxypsoralen as photosensitizer in combination with interferon alfa-2a subcutaneously 3 times a week in the maximal tolerable dosage (ie, up to 18 × 10⁶ U). The effects were investigated by a skin score, staging, histologic score (density of the T-cell infiltrate; from 0 = absent to 3 = heavy), immunohistology, and laboratory investigations including total peripheral T-cell count, CD4/CD8 ratio, and soluble interleukin 2 receptor (sIL-2R). Results: After 6 months, best response was a complete response (CR) in 4 patients, a partial response (PR) in 3, and a stable disease (SD) in 7 of 14 patients (overall response rate [CR + PR] 50%). In responders the time to best response was 4.3 ± 1.4 months. The skin score decreased from 22.5 ± 8.1 to 15.1 ± 11.0 (P < .001), the histologic score decreased from 2.57 ± 0.51 to 1.21 ± 0.80 (P < .001). In the lesional skin the percentage of CD4 cells decreased from 75% to 51% (P = .038) and Ki-67-positive cells decreased from 6.7% to 2.4% (P = .001). The total T-cell count/μL decreased from 1018.9 ± 557.1 to 667.9 ± 417.9 (P = .012), and the CD4/CD8 ratio also decreased from 1.88 ± 0.92 to 1.51 ± 0.67 (P = .038). The sIL-2R levels did not change significantly during the first 4 months of treatment. Among patients of stage IIa the response rate was 60% in contrast to only 25% of those in stage IIb. Side effects were seen temporarily, ranging from grade 0 to grade 3. There was no need for additional therapy, but interferon dose was decreased because of side effects. After 1 year of follow-up the total response rate was 46.2% (6 of 13 patients): 5 of 9 with stage IIa(55.6%) and 1 of 4 with stage IIb (25.0%). Conclusion: These results indicate that patients with CTCL stage IIa can achieve a total response rate of 56% with combined interferon alfa-2a and extracorporeal photochemotherapy. Responders seem to experience their best response within the first 6 months of treatment. The treatment is well tolerated and does not cause severe side effects. (J Am Acad Dermatol 2001;44:253-60.)