Alveolar macrophages (aMs) play a central role in respiratory host defense by sensing microbial antigens and initiating immune-inflammatory responses early in the course of an infection. The purpose of this study was to investigate the effect of cigarette smoke exposure on aMs following stimulation of innate pattern recognition receptors (PRRs) in a murine model. To accomplish this, C57Bl/6 mice were exposed for 8 weeks using two models of cigarette smoke-exposure, nose-only or whole-body exposure, and aMs isolated from the broncho-alveolar lavage. Following stimulation of aMs with pI:C, a mimic of viral replication, and bacterial cell-wall constituent LPS, aMs from cigarette smoke-exposed mice produced significantly attenuated levels of the inflammatory cytokines TNF and IL-6, and the chemokine RANTES. This attenuation was specific to the aM compartment, and not related to changes in aM viability or expression of TLR3 or TLR4 between groups. Furthermore, aMs from smoke-exposed mice had decreased cytokine RNA as compared to aMs from sham-exposed mice. Mechanistically, this was associated with decreased nuclear translocation of the pro-inflammatory transcription factor NFB and increased AP-1 nuclear translocation, in aMs from smoke-exposed mice. Attenuated cytokine production was reversible following smoking cessation. Cigarette smoke-exposure also attenuated TNF production following stimulation with NOD-Like receptor agonists, showing the effect applies more broadly to other PRR pathways. Our data demonstrate that cigarette smoke-exposure attenuates aMs responses following innate stimulation, including pathways typically associated with bacterial and viral infections.