Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 days postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor ([NK.sub.1]R), which is the respiratory rhythm generator, have not been explored. Body temperature, weight, ventilation, and arterial blood pH and gases were measured at 0, , and 6 dpi in control, lethal HK483, and nonlethal HK486 viral-infected mice. Immunoreactivities (IR) of PBC [NK.sub.1]R, H5N1 viral nucleoprotein (NP). and active caspase-3 (CASP3; a marker for apoptosis) were detected at 6 dpi. HK483. but not HK486, mice showed the following abnormalities: 1) gradual body weight loss and hypothermia; 2) tachypnea at 2-4 dpi and ataxic breathing with long-lasting apneas and hypercapnic hypoxemia at 6 dpi: and 3) viral replication in PBC [NK.sub.1]R neurons with [NK.sub.1]R-IR reduced by 75% and CASP3-IR colabeled at 6 dpi. Lethal H5N1 viral infection causes tachypnea at the early stage and ataxic breathing and apneas (hypercapnic hypoxemia) leading to death at the late stage. Its replication in the PBC induces apoptosis of local [NK.sub.1]R neurons, contributing to ataxic breathing and respiratory failure. lethal viral infection; respiratory rhythm; respiratory failure; hypoxemia; apoptosis doi: 10.1152/ajplung.00145.2017.