Preclinical data suggest that topical methyl aminolevulinate photodynamic therapy may have potential in preventing new skin lesions in transplant recipients. An open intra-patient randomized study investigated the prevention potential of this treatment in 27 renal transplant patients with actinic keratoses and other skin lesions in two circular contralateral areas (5 cm diameter). The treatment area surface was debrided and methyl aminolevulinate cream (160 mg/g) was applied for 3 h prior to illumination by non-coherent red light (570-670 nm, light dose 75 J/cm2). The control area was not treated. The mean time to occurrence of the first new lesion was significantly longer in treated than control areas (9.6 vs 6.8 months, treatment difference 2.9 [95% confidence interval 0.2 to 5.5] months, p = 0.034). Over 12 months, 62% (16/26) of treated areas were free from new lesions compared with 35% (9/26) in control areas. These findings indicate that topical methyl aminolevulinate photodynamic therapy is a promising preventive treatment against new skin lesions in immunosuppressed patients.