Photodynamic therapy (PDT) positively influences wound healing in animal models but the mechanism is unknown. We have examined the impact of PDT on wound healing in human skin and explored its potential modulation of leucocyte infiltration and inflammatory cytokine production. Wounds were created by 4mm punch biopsy in duplicate on the inner upper arms of healthy older men (60-77 years, n=18). One wound was treated immediately with methyl aminolevulinate (MAL)-PDT with repeat of this intervention on days 2 and 4, while the control wound was untreated. Wounds were re-excised by 6mm biopsy at 7 days (n=10 subjects) or 3 weeks (n=8) to investigate effects on the inflammatory phase and matrix deposition/remodelling phase respectively. At 7 days, MAL-PDT resulted in an augmented neutrophilic infiltrate with significantly reduced re-epithelialisation (35% vs 94% in control wounds, p<0.05) and apparent increased expression of IL6 and IL8. At 3 weeks, numbers of macrophages were increased in treated wounds (294±68 vs 69±25 cells mm -2 , p<0.05). Interestingly, they expressed the alternatively activated macrophage markers Ym1 and Fizz1. Treated wounds also tended towards a smaller area (p=0.07) with fewer cells mm -2 producing the proinflammatory macrophage migration inhibitory factor (MIF, p=0.06). Treated wounds were significantly closer in appearance to normal skin with respect to erythema (median score 1 vs 2 where 0=normal skin, p<0.05), colour (1 vs 2.5, p<0.05), and on global assessment (0 vs 1, p<0.05). Thus, MAL-PDT initially delays re-epithelialisation with apparently increased inflammation but after 3 weeks, treated wounds appear to show an increased rate of healing and significantly improved clinical appearance.