Production of histamine in colon tumours has been described earlier. Histamine-mediated signals have been shown to be implicated in tumour growth, and the effects of histamine are largely determined locally by the histamine receptor expression pattern. We analysed histamine receptor expression in human colorectal cancer, adenoma and normal mucosa by quantitative reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunostaining. Real-time RT-PCR results revealed significantly decreased (p<0.001) H1R and H4R mRNA levels in tumours compared to normal colonic mucosa, without any significant change in H2R mRNA expression. H3R was absent in most samples; it was detected at low levels in 7.9% of the cases. Protein analysis showed a similar decrease in histamine receptor expression in carcinoma and adenoma compared to normal mucosa controls. Based on these results, we performed further Western blot analysis on Dukes-classified and -selected tumour samples. We found significantly decreased H4R levels in neoplastic samples compared to normal colonic tissue, but there was no significant correlation between histamine receptor expression profile and the Dukes stage of tumours. Immunohistochemical staining revealed expression patterns of H1R, H2R and H4R similar to those suggested by the mRNA and Western blot results. In the present study, we demonstrate that H1R, H2R and H4R are expressed in colon carcinoma and the adjacent normal mucosa. The results suggest a dramatic alteration in the distribution of histamine receptors in colon cancer. These findings raise the perspective of targeted pharmacological studies with selective histamine receptor antagonists or agonists in the therapy of colorectal tumours.