Capsaicin, a major pungent constituent of red pepper (Capsicum annuum L.) possesses a vast variety of pharmacologic and physiologic activities. Despite its irritant properties, the compound exerts anti-inflammatory and anti-nociceptive effects. Previous studies from this laboratory revealed that capsaicin, when topically applied onto dorsal skin of female ICR mice, strongly attenuated activation of NF-kB and AP-1 induced by the typical tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), which may account for its anti-tumor promoting activity in mouse skin. In the present work, we have found that capsaicin suppresses TPA-stimulated activation of NF-kB through inhibition of $IkB{alpha}$ degradation and blockade of subsequent nuclear translocation of p65 in human pro myelocytic leukemia HL-60 cells. Methylation of the phenolic hydroxyl group of capsaicin abolished its inhibitory effect on NF-kB DNA binding. Likewise, TPA-induced activation of AP-1 was mitigated by capsaicin treatment.