The incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in previously healthy individuals has increased in the past 5 years. Such infections are associated with bronchiectasis and high mortality rates, making them a significant public health concern. The mechanisms of host defense against this pathogen are not well characterized. However, patients diagnosed with MRSA, as opposed to methicillin-susceptible S. aureus (MSSA), are more likely to have abused alcohol in the past, and these patients are more likely to die from sepsis. In the United States, USA300 is the predominant strain that causes necrotizing pneumonia. To investigate whether acute ethanol exacerbates MRSA pneumonia, mice were intraperitoneally (i.p.) administered 2 or 4 g/kg of ethanol 30 min prior to oropharyngeal inoculation of 2 × 10(7) CFU of USA300. An increased pulmonary bacterial burden was observed in alcohol-intoxicated mice at 16 and 24 h and was associated with decreased levels of interleukin 6 (IL-6). IL-6 activates signal transducer and activator of transcription 3 (STAT3) as part of an acute-phase response of infection. Reg3γ is an antimicrobial C-type lectin that is induced by STAT3 signaling in response to Gram-positive bacteria. Previously, in situ hybridization studies showed that Reg3g is highly expressed in lung epithelium. In the present study, we found that acute ethanol exacerbated USA300 in a murine model of USA300 pneumonia. This was associated with reduced IL-6 expression in vivo as well as inhibition of IL-6 induction of STAT3 signaling and Reg3g expression in mouse lung epithelial (MLE12) cells in vitro. Furthermore, recombinant Reg3γ administration 4 h after MRSA infection in alcohol-intoxicated mice rescued USA300 clearance in vivo. Therefore, acute alcohol intoxication leads to decreased MRSA clearance in part by inhibiting IL-6/STAT3 induction of the antimicrobial protein Reg3γ in the pulmonary epithelium.