<jats:p>We investigated effects of molecular hydrogen (H2) supplementation on acid-base status, pulmonary gas exchange responses, and local muscle oxygenation during incremental exercise. Eighteen healthy, trained subjects in a randomized, double-blind, crossover design received H2-rich calcium powder (HCP) (1500 mg/day, containing 2.544 µg/day of H2) or H2-depleted placebo (1500 mg/day) for three consecutive days. They performed cycling incremental exercise starting at 20-watt work rate, increasing by 20 watts/2 min until exhaustion. Breath-by-breath pulmonary ventilation (V˙E) and CO2 output (V˙CO2) were measured and muscle deoxygenation (deoxy[Hb + Mb]) was determined via time-resolved near-infrared spectroscopy in the vastus lateralis (VL) and rectus femoris (RF). Blood gases’ pH, lactate, and bicarbonate (HCO3−) concentrations were measured at rest and 120-, 200-, and 240-watt work rates. At rest, the HCP group had significantly lower V˙E, V˙CO2, and higher HCO3−, partial pressures of CO2 (PCO2) versus placebo. During exercise, a significant pH decrease and greater HCO3− continued until 240-watt workload in HCP. The V˙E was significantly lower in HCP versus placebo, but HCP did not affect the gas exchange status of V˙CO2 or oxygen uptake (V˙O2). HCP increased absolute values of deoxy[Hb + Mb] at the RF but not VL. Thus, HCP-induced hypoventilation would lead to lower pH and secondarily impaired balance between O2 delivery and utilization in the local RF during exercise, suggesting that HCP supplementation, which increases the at-rest antioxidant potential, affects the lower ventilation and pH status during incremental exercise. HPC induced a significantly lower O2 delivery/utilization ratio in the RF but not the VL, which may be because these regions possess inherently different vascular/metabolic control properties, perhaps related to fiber-type composition.</jats:p>