Background Patients with a previous medical history of nonmelanoma skin cancers (NMSCs) often develop multiple or recurrent malignant lesions around the site of the primary tumour. This finding led to the field cancerization theory, which suggests that the entire epithelial surface of the regional skin has an increased risk for the development of malignant lesions. Management of field change is challenging, taking into account the high impact of NMSCs on public health and healthcare costs. Objectives We sought to investigate whether field-photodynamic therapy (PDT) of extreme photodamaged skin would prevent new NMSCs, in comparison with a control area receiving placebo-PDT, in patients with clinical and histological signs of field cancerization. Methods Forty-five patients, previously diagnosed as having NMSCs of the face or scalp, with actinic keratoses symmetrically distributed over the same regions, were randomized for field treatment with 20% aminolaevulinic acid (ALA)-PDT on one side and placebo-PDT on the other. During the next 12-month period of follow up, patients were clinically evaluated for new NMSCs. Results A significant delay in the mean time of appearance and a reduction in the total number of new lesions were observed in the field-PDT protocol, when compared with the control. Conclusions The results obtained showed that field therapy with ALA-PDT confers a significant preventive potential against the formation of new NMSCs in patients with field changes.