Histidine decarboxylase (HDC) is the single enzyme responsible for histamine synthesis. HDC-deficient mice (HDC−/−) have no histamine in their tissues when kept on a histamine-free diet. Therefore, the HDC−/− mice provide a suitable model to investigate the involvement of histamine in the regulation of histamine receptor expression. Gene expression of H1 and H2 histamine receptors was studied in several organs of HDC−/− mice and compared to standard (HDC+/+) mice. In many tissues, prolonged absence of histamine induced down-regulation of the H2 receptor subtype. The expression of the H1 receptor was less sensitive to histamine deficiency. Exogenous histamine present in the diet abolished the differences observed in H2 receptor expression. These results suggest that the expression of mouse H2 receptor is under the control of histamine in a tissue-specific manner.