Keratinocytes from normal human skin were propagated in vitro. Histamine at 2 times 10(-6) M inhibited mitosis 68%. The side-chain methylated analogs, n-methylhistamine and n,n-dimethylhistamine, produced an inhibitory response of 53 and 60%, respectively, at 1 times 10(-6) M. The side-chain acetylated analog, n-acetylhistamine, did not elicit an inhibitory response in concentrations as high as 1 times 10(-4) M. The ring-methylated analogs, 1-methylhistamine and 4-methylhistamine, produced some degree of mitotic inhibition at 1 times 10(-4) M. When the H1-blocking agent, pyrilamine, or the H2-blocking agent, metiamide, was added in conjunction with histamine, the histamine-induced mitotic inhibition was abolished. These data indicate that human keratinocytes may possess receptors for histamine which could play a role in the regulation of human keratinocyte proliferation in vivo.