In a study of the direct effects of interferon-gamma (IFN-γ) on normal human skin, healthy adult male volunteers received either 3 μg (n=4) or 30 μg (n=9) of recombinant IFN-γ administered intradermally over 3 days. Biopsies were taken on day 6 and histopathological examination of fixed paraffin-embedded sections from sites which had received 30 μg IFN-γ revealed a moderate perivascular lymphohistiocytic dermal infiltrate with mast cells. Immunophenotyping of 5 μm cryostat sections demonstrated that 3 μg IFN-γ induced keratinocyte HLA-DR expression in the absence of any significant infiltrate. More intense keratinocyte HLA-DR expression was produced by 30 μg IFN-γ in all specimens, with HLA-DP concurrently expressed in three biopsies. The ratio of CD4:CD8 cells within the infiltrate was approximately 3:1. CD1+ cells within the epidermis were markedly depleted by 30μg IFN-γ, while CD1-labelled cells were observed in the dermal perivascular infiltrate. Intradermal IFN-γ induces similar immunopathological changes to those observed in many of the inflammatory dermatoses.