Gelfand, R., C. J. Lambertsen, J. M. Clark, and E. Hopkin. Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI). J. Appl. Physiol. 84(1): 292-302, 1998.Potential adverse effects on the O₂-sensing function of the carotid body when its cells are exposed to toxic O₂ pressures were assessed during investigations of human organ tolerance to prolonged continuous and intermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxic ventilatory responses (HVR) were determined at 1.0 ATA before and after severe hyperoxic exposures: 1) continuous O₂ breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and 2) intermittent O₂ breathing at 2.0 ATA (30 min O₂-30 min normoxia) for 14.3 O₂ h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared with preexposure controls. The hyperbolas were temporarily elevated to higher ventilations than controls due to increments in respiratory frequency that were proportional to O₂ exposure time, not O₂ pressure. In humans, prolonged hyperoxia does not attenuate the hypoxia-sensing function of the peripheral chemoreceptors, even after exposures that approach limits of human pulmonary and central nervous system O₂ tolerance. Current applications of hyperoxia in hyperbaric O₂ therapy and in subsea- and aerospace-related operations are guided by and are well within these exposure limits.