Histamine depressed lymphocyte reactivity to phytohemagglutinin and, to a lesser degree, concanavalin A, when administered simultaneously with mitogen to lymphocyte Cultures. Addition of histamine at later times to the cultures appeared to have a slightly enhancing effect on the lymphocyte response. Stimulation of lymphocytes with pokeweed mitogen was in some CMM enhanced, even by high concentrations of Lymphocytes. Lymphocytes from atopic individuals were more sensitive to the inhibitory effect of histamine than Lymphocytes from nonatopic individuals. The sensitivity appeared age‐dependent, but within each age group histamine evoked significantly more suppression on lymphocytes from atopic than from nonatopic individuals. The possibility that the altered reactivity of lymphocytes to histamine, which appears to be associated with atopic allergy, is of pathogenic importance, is discussed, and a hypothesis for the development of atopic disease is proposed.