Impaired host defense after alcohol use is linked to altered cytokine production, however, acute and chronic alcohol differently modulate monocyte/macrophage activation. We hypothesized that in human monocytes, acute alcohol induces hyporesponsiveness to LPS, resulting in decreased TNF-alpha, whereas chronic alcohol increases TNF-alpha by sensitization to LPS. We found that acute alcohol increased IL-1R-associated kinase-monocyte (IRAK-M), a negative regulator of IRAK-1, in human monocytes. This was associated with decreased IkappaB alpha kinase activity, NFkappaB DNA binding, and NFkappaB-driven reporter activity after LPS stimulation. In contrast, chronic alcohol decreased IRAK-M expression but increased IRAK-1 and IKK kinase activities, NFkappaB DNA binding, and NFkappaB-reporter activity. Inhibition of IRAK-M in acute alcohol-exposed monocytes using small interfering RNA restored the LPS-induced TNF-alpha production whereas over-expression of IRAK-M in chronic alcohol macrophages prevented the increase in TNF-alpha production. Addition of inhibitors of alcohol metabolism did not alter LPS signaling and TNF-alpha production during chronic alcohol exposure. IRAK-1 activation induces MAPKs that play an important role in TNF-alpha induction. We determined that acute alcohol decreased but chronic alcohol increased activation of ERK in monocytes and ERK inhibitor, PD98059, prevented the chronic alcohol-induced increase in TNF-alpha. In summary, inhibition of LPS-induced NFkappaB and ERK activation by acute alcohol leads to hyporesponsiveness of monocytes to LPS due to increased IRAK-M. In contrast, chronic alcohol sensitizes monocytes to LPS through decreased IRAK-M expression and activation of NFkappaB and ERK kinases. Our data indicate that IRAK-M is a central player in the opposite regulation of LPS signaling by different lengths of alcohol exposure in monocytes.