Background A relationship between excessive daytime sleepiness (EDS) and poor treatment adherence has been suspected but not confirmed. We hypothesized that medication adherence would be poorer in adults with heart failure (HF) and EDS and that cognitive status would be the mechanism of effect. Methods and Results A sample of 280 adults with chronic HF were enrolled into a prospective cohort comparison study. We identified a cohort with EDS and a control group without EDS and further divided both groups into those with and without mild cognitive decline. Data on medication adherence were obtained at baseline and 3 and 6 months by using the Basel Assessment of Adherence Scale. Regression analysis was used to clarify the contribution of EDS and cognition to medication adherence and to assess relationships over 6 months after adjusting for age, enrollment site, gender, race, functional class, depression, and premorbid intellect. At baseline, 62% of subjects were nonadherent to their medication regime. Nonadherence was significantly more common in those with EDS, regardless of cognitive status (P = .035). The odds of nonadherence increased by 11% for each unit increase in EDS (adjusted odds ratio 1.11; 95% confidence interval 1.05–1.19; P = .001). In longitudinal models, there was a 10% increase in the odds of nonadherence for each unit increase in EDS (P = .008). The only cognition measure significantly associated with medication adherence was attention (P = .047). Conclusions Adults with HF and EDS are more likely to have problems adhering to their medication regimen than those without EDS, regardless of their cognitive status. Identifying and correcting factors that interfere with sleep may improve medication adherence.