Histone deacetylase 6 (HDAC6) is a class II histone deacetylase that is predominantly localized in the cytoplasm of cells. HDAC6 associates with microtubules, regulating acetylation of tubulin and other proteins. The possibility that HDAC6 participates in hypoxic signaling is supported by evidence that (1) hypoxic gas challenges cause microtubule depolymerization, (2) expression of hypoxia inducible factor alpha (HIF)-1α is regulated by microtubule alterations in response to hypoxia, and (3) inhibition of HDAC6 prevents HIF-1α expression and protects tissue from hypoxic/ischemic insults. The aim of this study was to address whether the absence of HDAC6 alters ventilatory responses during and/or after hypoxic gas challenges (10% O2, 90% N2for 15 min) in adult male wild-type (WT) C57BL/6 mice and HDAC6 knockout (KO) mice. Key findings were that (1) baseline values for frequency of breathing, tidal volume, inspiratory and expiratory times and end expiratory pause were different between KO mice and WT mice, (2) ventilatory responses during hypoxic challenge were more robust in KO mice than WT mice for parameters including frequency of breathing, minute ventilation, inspiratory and expiratory durations, peak inspiratory and expiratory flows, inspiratory and expiratory drives, and (3) responses upon return to room-air were markedly different in KO mice than WT mice for frequency of breathing, minute ventilation, inspiratory and expiratory durations, end expiratory (but not end inspiratory) pauses, peak inspiratory and expiratory flows, and inspiratory or expiratory drives. These data suggest that HDAC6 may have a fundamentally important role in regulating the neural responses to hypoxia.