We investigated the effect of alcohol (ethanol) on the ability of the alveolar macrophage to produce tumor necrosis factor-α (TNF-α), superoxide anion (O2−), and nitric oxide (NO)—three critical components of pulmonary host defense. Male rats were treated with alcohol either acutely (priming dose 175 mg/100 g of body weight, followed by a 7-hr continuous intravenous infusion of 30 mg/100 g of body weight/hr) or chronically (12–14 weeks of feeding ethanol in a liquid diet). Three hours before sacrifice, the rats received an intravenous injection of saline or lipopolysaccharide (LPS; Escherichia coli, 026:B6, 100 μg/100 g of body weight). Alveolar macrophages (AMs) were then isolated by bronchoalveolar lavage and assessed for their in vitro capacity to produce TNF-α, O2−, and NO spontaneously and in response to different stimuli. Acute alcohol administration suppressed in vitro LPS-stimulated AM TNF-α secretion by 52%. AMs from both pair- and alcohol-fed rats secreted TNF-α spontaneously in culture. However, the AMs from chronic alcohol-fed group secreted 42–53% less TNF-α spontaneously and in response to LPS, interferon-γ (IFN-γ) or IFN-γ+ LPS compared with the AMs from pair-fed group. Systemic LPS treatment inhibited in vitro-LPS-stimulated AM TNF-α secretion (50%) only in the control rats. Acute alcohol administration enhanced significantly in vitro phorbol 12-myr-istate 13-acetate (PMA)- and opsonized zymosan (OPZ)-induced AM O2− secretion (4- and 1.8-fold, respectively). Systemic LPS treatment primed the AMs from control rats to secrete 83% more O2− in response to PMA but not OPZ; however, in the acute alcohol-treated group, it suppressed both PMA (54%)- and OPZ (66%)-induced AM O2− release (loss of priming effect of LPS). Chronic alcohol feeding suppressed PMA-induced AM O2− secretion (40%) without affecting the OPZ-induced release. Although systemic LPS treatment had no significant effect on PMA or OPZ-induced AM O2− secretion in the pair-fed group, it enhanced the PMA-stimulated AM O2− release (88%) in the alcohol-fed group. AMs recovered from control or acute alcohol-treated rats did not secrete NO spontaneously in vitro. However, AMs from both pair and chronic alcohol-fed rats secreted NO spontaneously with AMs from chronic alcohol-fed group secreting 34% less. Both acute and chronic alcohol treatment inhibited AM NO secretion in response to IFN-γ, LPS, and IFN-γ+ LPS significantly. Systemic LPS had no effect on AM NO production in response to different in vitro stimuli in any of the treatment groups. These data suggest that: (1) both acute and chronic alcohol administration to rats inhibit AM TNF-α and NO secretion; (2) acute and chronic alcohol treatment have differential effects on AM O2− secretion; and (3) alcohol-induced alteration in AM TNF-α, O2−, and NO secretion may in part explain the increased susceptibility of alcohol-consuming individuals to pulmonary infections.