Summary Background Topical photodynamic therapy (PDT) elicits a therapeutic response in both skin cancer and immune-mediated skin disorders. While PDT induces direct cell death, host inflammatory and immune responses to PDT may contribute to the therapeutic effects. Objectives To examine the impact of topical PDT on leucocyte trafficking and mediators of chemotaxis in healthy human skin. Methods Aminolaevulinic acid (ALA)-PDT was performed on the buttock skin of seven healthy volunteers. Biopsies for immunohistochemical assessment were taken 1, 4 and 24 h post-PDT and from untreated contralateral buttock skin (baseline). Results A significant dermal neutrophilic infiltrate appeared early, peaking at 4 h (P <0·01) and returning to near baseline by 24 h. Expression of E-selectin was significantly higher at 4 h (P <0·05) and correlated strongly with neutrophil numbers (r = 0·93). Expression of intercellular adhesion molecule 1 was significantly elevated after 24 h (P <0·05) with an apparent gradual increase in CD4+ T cells up to this time point. Notably, epidermal Langerhans cells were significantly reduced 24 h post-PDT compared with baseline (P <0·01) and comprised a significantly larger proportion of cells with migratory rather than dendritic morphology (P <0·05). The number of epidermal cells expressing tumour necrosis factor-α significantly increased at 4 h (P <0·05) and remained elevated 24 h post-PDT, whereas no significant change in expression of interleukin (IL)-1β or IL-8 was seen. Conclusions Reduction of Langerhans cells by topical PDT of human skin may play a significant role in PDT-induced local immunosuppression, potentially benefiting the treatment of immune-mediated skin disorders but negatively impacting on antitumour responses. Further exploration according to disease indication/treatment protocol is warranted. © 2011 British Association of Dermatologists.