Histamine, produced by dendritic cells (DCs) or by other cells of the immune system, may have significant impact on DC activities. We investigated the influence of histamine and histamine H4 receptor (H4R) on some relevant functions of DCs. Histamine significantly decreased the antigen presentation capacity of splenic DCs, and this effect was reversed by a H4R antagonist. Furthermore, enhanced antigen presentation was detected in H4R-/- DCs. Prolonged histamine treatment during DC differentiation stimulated migration, albeit the increase was not significant. H4R-deficient DCs possessed significantly lower migration capacity than their wild-type counterparts. Monitoring in vivo and in vitro DC cytokine production revealed that a H4R agonist in combination with LPS, increased IL-1 beta mRNA expression, and a H4R antagonist reversed this effect. In H4R-deficient mice we detected decreased mRNA expression of some DC-derived cytokines including IFN-gamma and IL-10. Upon CFA stimulation, genotype-dependent differences were found in the expression of IL-6 and IFN-gamma. Our data suggest that H4R plays a crucial role in variety of functions of murine DCs.