Pseudomonas aeruginosa causes severe infections, particularly of the lung, that are life threatening. Here, we show thatP. aeruginosa infection induces apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95 ligand system. Deficiency of CD95 or CD95 ligand on epithelial cells prevented apoptosis of lung epithelial cells in vivo as well as in vitro. The importance of CD95/CD95 ligand–mediated lung epithelial cell apoptosis was demonstrated by the rapid development of sepsis in CD95- or CD95 ligand–deficient mice, but not in normal mice, afterP. aeruginosa infection.