AbstractA number of representative flavonoids reversibly inhibit human lymphocyte proliferative responses in a concentration-dependent manner. The flavonoids quercetin and tangeretin are most effective when added during the early phase of exposure of lymphocytes to the mitogenic stimuli but become progressively less effective when added after increasing lengths of time following stimulation, suggesting an early flavonoid-sensitive step(s) in cell activation. In the proliferative response to phytomitogens, they do not act by inhibiting the early increase in calcium influx. They do not augment cellular cyclic-AMP concentration in basal or phytomitogen-stimulated lymphocytes nor reduce its increment in the presence of inhibitors of phosphodiesterase. At concentrations inhibitory to the proliferative response, quercetin (but not tangeretin) inhibits the calcium-activated, phospholipid-dependent protein kinase (C kinase). Certain flavonoids powerfully inhibit the uptake of thymidine into phytomitogen-stimulated lymphocytes but do not directly affect incorporation of already transported thymidine into newly synthesized DNA.