Canine cutaneous histiocytoma is a benign epidermal neoplasm of Langerhans cell origin, which usually displays spontaneous regression. Based on the degree of lymphocytic infiltration, 30 histiocytomas were classified into four groups representing different stages of tumour regression. To elucidate further the mechanisms of the antitumour immune response CD3+, CD21+, CD4+, CD8+ and myeloid/histiocyte antigen+ inflammatory cells were differentiated by immunohistochemistry and quantified. In addition, the number of apoptotic cells was detected using the TdT-mediated biotin–dUTP nick-end labelling (TUNEL) method. Furthermore, the expression of interleukin- (IL-2), IL-12(p40), tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-10 and transforming growth factor-β (TGF-β) as well as inducible nitric oxid synthase (iNOS) mRNA was determined by reverse transcription–polymerase chain reaction (RT–PCR). Phenotyping of inflammatory cells revealed a significantly increased infiltration of all lymphocyte subsets and myeloid/histiocytic cells with the onset of tumour regression. The latter was significantly correlated to up-regulation of IL-2, TNF-α, IFN-γ and iNOS mRNA expression. Expression of remaining cytokines and percentage of apoptotic cells showed no group-specific changes. The results indicate an initial infiltration of CD4+ T cells followed by increased expression of Th1 cytokines and recruitment of antitumour effector cells as the principal mechanism for tumour regression. Canine cutaneous histiocytoma is a unique example for an effective immune response in a naturally occurring neoplasm derived from epidermal Langerhans cells and might represent a valuable animal model to investigate tumour immunity.