We hypothesized that individuals with untreated obstructive sleep apnea (OSA) would exhibit greater vulnerability to sleep deprivation than healthy controls, due to the additional neurobiological 'load' of chronic sleep fragmentation. After baseline sleep with 8 h time in bed, participants remained awake for 40 h. Psychomotor Vigilance Task (PVT, mean slowest 10% 1/RT), AusEd Driving Simulator task (steering and speed deviation), and subjective sleepiness (Karolinska Sleepiness Scale, KSS) were assessed every 2 h. Nonlinear mixed-effects models were used to characterize individual differences in baseline/average performance, the linear effect of increasing hours awake, circadian amplitude and phase. Eight participants with untreated OSA with mean (SD) age 44.6 (8.4), apnea-hypopnea index (AHI) 49.8 (24.7), Epworth Sleepiness Scale (ESS) 11.9 (4.8) and nine healthy controls age 27.8 (3.7), AHI 4.5 (2.7), ESS 7.3 (2.1) completed the protocol. Baseline KSS was significantly higher (1.4 units, P = 0.03) in the OSA group and there was a trend toward lower baseline speed deviation on the AusEd (P = 0.05). After adjusting for the significant effects of accumulated time awake, circadian amplitude and phase (all P < 0.005), there was no difference in performance decrements between those with and without sleep apnea in PVT, driving simulator performance and subjective sleepiness (P > 0.5). Random-effects modeling confirmed the presence of significant inter-individual variability in vulnerability to sleep deprivation. Patients with OSA did not respond differently to sleep deprivation than healthy controls. As expected, total sleep deprivation led to significant worsening in performance and subjective sleepiness in both groups.