BACKGROUND AND OBJECTIVES Squamous cell carcinomas (SCCs) produce significant morbidity in solid organ transplant recipients (SOTRs), particularly in patients who develop multiple tumors. Topical photodynamic therapy (PDT) has been shown to decrease the number of keratotic lesions in SOTRs, but the duration of the beneficial effect is limited. The aim of this study was to evaluate the potential benefit of cyclic PDT in the prevention of new SCCs in SOTRs. METHODS Twelve high-risk SOTRs received cyclic PDT treatments at 4- to 8-week intervals for 2 years. The development of new SCCs (invasive and in situ) performed 12 and 24 months after the start of cyclic PDT were compared with the number of SCCs developed during the year before initiation of cyclic PDT. RESULTS The median reduction in the 12- and 24-month post-treatment counts from the 1-month pretreatment counts was 79.0% (73.3-81.8%) and 95.0% (87.5-100.0%), respectively. Treatments were well tolerated. CONCLUSION Cyclic PDT with 5-aminolevulinic acid may reduce the incidence of SCC in SOTRs. Additional studies with larger numbers of patients and optimized protocols are necessary to further explore the potential benefits of cyclic PDT in the prevention of skin cancer in this high-risk patient population. Dr. Lee is member of the Medical Advisory Board of Dusa Pharmaceuticals, Inc.