Clinical data underscores the fact that subsequent high mortality rates occur in patients who survive acute septic episodes. Herein, we described a clinically relevant model of experimental sepsis that we believe will allow further investigation of the manner in which the pulmonary innate immune response is modulated after sepsis. C57BL/6 mice were subjected to cecal ligation and puncture (CLP) model, whereby the cecum was partially ligated and punctured nine times with a 21-gauge needle. This procedure was associated with 100% mortality at 3 days after surgery. In contrast, when mice subjected to CLP were treated with antibiotic beginning at 8 hours after surgery, and every 12 hours thereafter until 3 days, approximately 60% of the mice survived. Interestingly, CLP survivors quickly succumbed (100% mortality) to pulmonary infection when intratracheally challenged, at day 3 after CLP, with viable Aspergillus fumigatus conidia. No mortality was observed in conidia-challenged sham-operated mice. The defective innate immune response against A. fumigatus in CLP mice could not be explained by a failure of neutrophils to infiltrate the lungs. Instead, gene array analysis revealed that several components of the innate immune response, including the nuclear factor-kappaB signaling pathway, were down-regulated. Thus, we describe a system of sepsis-induced innate immune failure in the lungs of C57BL/6 mice.