A randomized-controlled trial with paired observations was performed with 40 organ-transplant recipients to assess the preventive effect of photodynamic therapy (PDT) on the development of new squamous-cell carcinomas and to evaluate the effect of PDT on the number of keratotic skin lesions. The treatment area consisted of a randomly assigned forearm and the corresponding hand, whereas the other forearm and hand served as the control area. After the initial visit, follow-up visits were scheduled at 3-monthly intervals during 2 years. No statistically significant difference was found in the occurrence of new squamous-cell carcinomas between the treated and untreated arms: after 2 years of follow-up, we observed 15 squamous-cell carcinomas in nine out of 40 PDT-treated arms and 10 squamous-cell carcinomas in nine out of 40 control arms. The number of keratotic skin lesions increased in both arms, but was less pronounced in the PDT-treated arm. After 1 year of follow-up, a trend in favor of the PDT-treated arm was observed, but statistical significance was not reached. Nearly 80% of the patients reported mild to severe adverse effects consisting of pain and a burning sensation, immediately after the treatment. No long-term adverse events were noted. In conclusion, PDT does not appear to prevent the occurrence of new squamous-cell carcinomas in organ-transplant recipients, but to some degree, reduces the increase of keratotic skin lesions.