Immunosuppressive medication in renal transplant recipients (RTR) strongly increases the risk of cancers on sun-exposed skin. This increased risk was considered an inevitable collateral effect of immunosuppression, because UV-induced carcinomas in mice were found to be highly antigenic. Here, we posed the question whether immunosuppression also increases the frequency of p53-mutant foci ('p53 patches'), putative microscopic precursors of squamous cell carcinomas. As the majority of RTR was kept on azathioprine for most of the time, we investigated whether this drug could increase UV-induced p53 patches by immunosuppression. As azathioprine can impair UV-damaged DNA repair under certain conditions, we also investigated whether DNA repair was affected. Archive material of RTR and immunocompetent patients (ICP), as well as azathioprine-administered hairless mice were examined for p53 patches. DNA repair was investigated by ascertaining the effect of azathioprine on unscheduled DNA synthesis (UDS) in UV-irradiated human keratinocytes. P53 patches were more prevalent in RTR than in ICP in normal skin adjacent to carcinomas (P = 0.02), in spite of a lower mean age in the RTR (52 vs 63 years, P = 0.001), but we found no increase in UV-induced p53 patches in mice that were immunosuppressed by azathioprine. We found a significant reduction in DNA repair activity in keratinocytes treated with azathioprine (P = 0.011). UV-induced UDS in humans is dominated by repair of cyclobutane pyrimidine dimers, and these DNA lesions can lead to 'UV-signature' mutations in the P53 gene, giving rise to p53 patches.