Positive airway pressure (PAP) is the most common form of treatment for obstructive sleep apnea (OSA). Treatment adherence is notoriously low, and holidays from treatment are common. To date, there is no literature on the effects of acute withdrawal from PAP treatment on the brain activity of individuals with OSA. Nine participants with OSA performed a 2-Back verbal working memory paradigm during repeated functional magnetic resonance imaging (FMRI). Counterbalanced FMRI sessions were under conditions of PAP treatment (at least one consecutive week) or non-treatment (for two consecutive nights). Treatment effects on 2-Back-related brain activity were significant, with greater deactivation in the right posterior insula and overactivation in the right inferior parietal lobule. The observed responses to PAP treatment withdrawal were more extreme in all regions of interest, such that 2-Back-related activity increased and 2-Back-related deactivation decreased further relative to the 0-Back control task. The withdrawal of PAP treatment in effectively treated individuals with OSA might result in the need to reallocate resources in order to perform at the same cognitive level.