OBJECTIVE: To compare the efficacy and tolerability of a single ALA-PDT illumination scheme with that of a fractionated ALA-PDT illumination scheme in face and scalp actinic keratoses (AKs).METHODS: Eligible patients received either a single ALA-PDT illumination or a fractionated illumination scheme randomly allocated to alternate sides of face/scalp. The side allocated to a single illumination received 75 J/cm(2). This side received 2 sessions performed 7 days apart. Lesions on the fractionated illumination scheme side received 20 and 80 J/cm(2), 4 and 6 hours after a single ALA application. Patients were evaluated at baseline, at 3 and 12 months after treatment. Efficacy end point included the individual AK lesion clearance rate.RESULTS: Thirty three patients with 266 lesions were enrolled in the study. Three months after treatment the overall lesion complete response rate was 89.05% for the single scheme and 96.12% for the fractionation scheme while at the 12-months follow-up response rate decreased to 85.4% for the single illumination and to 93.79% for the fractionated illumination group. Looking at lesion response based on lesion grade fractionated photodynamic therapy (PDT) resulted in larger rates of cured grade I as well as grade II lesions. Recorded adverse events were transient and did not demand additional therapy.CONCLUSIONS: Our results demonstrate that higher responses are achieved with fractionated PDT compared with single illumination PDT. The study data indicate that fewer treatment sessions may be needed with fractionated PDT increasing that way the comfort of the patient regarding number of visits, treatment cost and treatment-related downtime.