Background: Decreased oxygenation of muscle may be accentuated during exercise at high altitude. Monitoring the oxygen saturation of muscle (SmO 2) during hand grip exercise using near infrared spectroscopy during acute exposure to hypoxia could provide a model for a test of muscle performance without the competing cardiovascular stresses that occur during a cycle ergometer or treadmill test. The purpose of this study was to examine and compare acute exposure to normobaric hypoxia versus normoxia on deoxygenation and recruitment of the flexor digitorum superficialis (FDS) during submaximal intermittent handgrip exercise (HGE) in healthy adults. Methods: Twenty subjects (11 M/9 F) performed HGE at 50% of maximum voluntary contraction, with a duty cycle of 2 s:1 s until task failure on two occasions one week apart, randomly assigned to normobaric hypoxia (FiO 2 = 12%) or normoxia (FiO 2 = 21%). Near-infrared spectroscopy monitored SmO 2 , oxygenated (O 2 Hb), deoxygenated (HHb), and total hemoglobin (tHb) over the FDS. Surface electromyography derived root mean square and mean power frequency of the FDS. Results: Hypoxic compared to normoxic HGE induced a lower FDS SmO 2 (63.8 ± 2.2 vs. 69.0 ± 1.5, p = 0.001) and both protocols decreased FDS SmO 2 from baseline to task failure. FDS mean power frequency was lower during hypoxic compared to normoxic HGE (64.0 ± 1.4 vs. 68.2 ± 2.0 Hz, p = 0.04) and both decreased mean power frequency from the first contractions to task failure (p = 0.000). Under both hypoxia and normoxia, HHb, tHb and root mean square increased from baseline to task failure whereas O 2 Hb decreased and then increased during HGE. Arterial oxygen saturation via pulse oximetry (SpO 2) was lower during hypoxia compared to normoxia conditions (p = 0.000) and heart rate and diastolic blood pressure only demonstrated small increases. Task durations and the tension-time index of HGE did not differ between normoxic and hypoxic trials.