This study aimed to quantify how acute hypoxia impacts firing characteristics of biceps brachii motor units (MUs) during sustained isometric elbow flexions. MU data were extracted from surface electromyography (EMG) during 25% maximal voluntary contractions (MVC) in 10 healthy subjects (age 22 ± 1 yr). Blood oxygen saturation (SpO2) was then stabilized at 80% by reducing 1% of the fraction of inspired oxygen every 3 min for 35 min. MU data were once again collected 1 h and 2 h following the 35-min desaturation phase. Although MVC remained unaffected during 2 h of 80% SpO2, subject-specific changes in MU firing rate were observed. Four of 10 subjects exhibited a decrease in firing rate 1 h postdesaturation (12 ± 11%) and 2 h postdesaturation (16 ± 12%), whereas 6 of 10 subjects exhibited an increase in firing rate 1 h (9 ± 6%) and 2 h (9 ± 4%) postdesaturation. These bidirectional changes in firing rate were strongly correlated to the desaturation phase and the subjects' SpO2 sensitivity to oxygen availability, where subjects who had decreased firing rates reached the target SpO2 20 min into the desaturation phase (R2 = 0.90-0.98) and those who had increased firing rates reached the target SpO2 35 min into the desaturation phase (R2 = 0.87-0.98). It is unlikely that a single mechanism accounted for these subject-specific changes in firing rate. Instead, differences in intrinsic properties of the neurons, afferent input to the motoneurons, neuromodulators, and sympathetic nerve activity may exist between groups. NEW & NOTEWORTHY The mechanisms of compromised motor control when exposed to hypoxia are largely unknown. The current study examined how severe acute hypoxia affects motor unit firing rate during sustained isometric contractions of the bicep brachii. The response to hypoxia was different across subjects, where motor unit firing rate increased for some individuals and decreased for others. This bidirectional change in firing rate was associated with how fast subjects desaturated during hypoxic exposure.