Background. Lethal influenza A (H5N1) induces respiratory failure in humans. Although it also causes death at 7 day postinfection (dpi) in mice, the development of the respiratory failure and the viral impact on pre-Botzinger complex (PBC) neurons expressing neurokinin 1 receptor (NK1R), the respiratory rhythm-generator, have not been explored. Methods. Body temperature, weight, ventilation, arterial blood pH and gases were measured at 0, 2, 4, and 6 dpi in control, lethal HK483 and non-lethal HK486 viral infected mice. Immunoreactivities (IR) of PBC NK1R, H5N1 viral nucleoprotein (NP), and active caspase-3 (CASP3, a marker for apoptosis) were detected at 6 dpi. Results. HK483, but not HK486, mice showed 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 NK1R neurons with NK1R-IR reduced by 75% and CASP3-IR co-labeled at 6 dpi. Conclusion. 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 NK1R neurons, contributing to ataxic breathing and respiratory failure.