Obstructive sleep apnea (OSA) is associated with the apolipoprotein E polymorphic allele ( ) and with worse cognitive function. However, the influence of on cognitive function in patients with moderate-to-severe OSA is controversial. The present study evaluated the influence of polymorphism and cognitive function in sedentary OSA patients with no other major comorbidities.  In total, 55 middle-aged patients underwent conventional nocturnal polysomnography, polymorphism genotyping, cognitive evaluation (attention, inhibitory control, frontal functions, processing speed, and episodic memory), and they filled out the International Physical Activity Questionnaire.  Overall, 13 patients had no or mild OSA, and 42 had moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥ 15 events/h of sleep) and was present in 7.7% and 21.4% of the patients in each group respectively. Among patients with moderate-to-severe OSA, the sleep parameters were similar in the groups of carriers and noncarriers. Compared with patients with no or mild OSA, the cognitive parameters were worse for processing speed (Digit Symbol Test) and attention (Stroop Color Word Test, SCWT-Part 2) among the patients with moderate-to-severe OSA. The difference was present even after the exclusion of carriers. Among patients with moderate-to-severe OSA, carriers presented worse episodic memory, evaluated through the Rey Auditory Verbal Learning Test, than noncarriers.  Moderate-to-severe OSA is associated with poor cognitive function that is further impaired by the presence of polymorphism.