This retrospective, observational study was conducted to determine overlap of prevalence between atrial fibrillation (AF), an increasingly common condition that primarily affects the elderly population, and dyspepsia, which is also common. Because the overlap of these conditions could interfere with health care including medication selection, the effect on patient outcomes was also evaluated. A demographically representative population of adults in the United States self-administered an Internet-based questionnaire, and responses were evaluated to determine the presence of AF and measures of comorbidity, including CHADS2 score of stroke risk. Health-related quality of life, work productivity and activity impairment, and health care resource utilization were also assessed. The impact of dyspepsia on these patient outcomes was then examined with multiple regressions and generalized linear models. From the sample population, 1297 participants reported being diagnosed with AF, of whom 34% (449/1297) reported diagnosis of dyspepsia. Those with dyspepsia had a higher mean CHADS2 score than those without dyspepsia. Despite this higher risk, significantly fewer AF patients with dyspepsia than those without dyspepsia were taking either prescription medication to treat AF or anticoagulants for stroke prevention. Dyspepsia was associated with significantly lower levels of both mental and physical health-related quality of life. Work and activity impairment and health care resource utilization were also significantly higher among AF patients with dyspepsia than among those without. The burden of dyspepsia in AF patients should be considered during medication selection. Selection of agents associated with lower rates of dyspepsia may lead to greater patient acceptance of and adherence to therapy.