Acetazolamide (ACZ), a carbonic anhydrase inhibitor, is used to manage periodic breathing associated with altitude and with heart failure. We examined whether ACZ would alter post-hypoxic ventilatory behavior in the C57BL/6J (B6) mouse model of recurrent central apnea. Experiments were performed with unanaesthetized, awake adult male B6 mice (n = 9), ventilatory behavior was measured using flow through whole body plethysmography. Mice were given an intraperitoneal injection of either vehicle or ACZ (40mg/kg), and one hour later exposed to 1-min of 8% O₂-balance N₂ (poikilocapnic hypoxia) or 12% O₂, 3% CO₂-balance N₂ (isocapnic hypoxia) followed by rapid reoxygenation (100% O₂). Hypercapnic response (8% CO₂-balance O₂) was examined in 6 mice. With ACZ, ventilation including respiratory frequency, tidal volume, and minute ventilation in room air were significantly higher and hyperoxic hypercapnic ventilatory responsiveness was generally lower compared to vehicle. Poikilocapnic and isocapnic hypoxic ventilatory responsiveness were similar among treatments. One minute after reoxygenation, animals given ACZ exhibited post-hypoxic frequency decline, a lower coefficient of variability for frequency, and no tendency towards periodic breathing, as compared to vehicle treatment. We conclude that ACZ improves unstable breathing in the B6 model, without altering hypoxic response or producing short-term potentiation, but with some blunting of hypercapnic responsiveness.