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Abstract Study Objectives Evidence is limited on the role of caffeine intake in the relationship between sleep quality and the incidence of major adverse cardiovascular events (MACE) particularly in patients with sleep breathing disorders. Therefore, this study’s primary aim was to determine the potential confounding effects of total caffeine consumption on the relationship between sleep quality parameters (total sleep time [TST], sleep efficiency [SE], sleep latency [SL], daytime sleepiness, and wakefulness after sleep onset [WASO]) and MACE. Methods This study is a secondary analysis of data from the Sleep Heart Health Study (SHHS). Sleep assessments (TST, SE, SL, daytime sleepiness, and WASO) were performed objectively using in-home polysomnography. Caffeine was measured using a survey asking about the average number of cups/cans/glasses of tea, soda, and coffee consumed per regular day and during the last night before polysomnography. Results A final sample of 5628 participants was included in SHHS Visit 1 (78% White/Caucasian; 54 % female). Cumulative incidence rates measured over 10.9±2.8 years were 15.1% for MACE and 19.7% for all-cause mortality. In univariate models, all sleep measures except SL were associated with MACE; but after adjustment, only TST remained a significant predictor (OR=1.122, p=.011). No confounding effect of caffeine was observed in the associations between sleep measures and MACE. Moderate-high intake attenuated MACE risk among individuals with greater daytime sleepiness (OR= 0.91, p =.011). Conclusions Caffeine was not a confounding factor in the relationship between sleep measures and MACE. While exploratory analyses suggested potential modification of the association between hypersomnolence and cardiovascular outcomes, these effects were attenuated after statistical adjustment and correction for multiple testing and should be interpreted cautiously. Statement of Significance In this secondary analysis of the Sleep Heart Health Study, we evaluated whether caffeine consumption confounds or moderates the associations between sleep, major adverse cardiovascular events (MACE), and all-cause mortality. Results indicate that caffeine does not significantly confound the role of sleep in predicting these outcomes. While caffeine intake showed a potential to modify the effect of daytime sleepiness on MACE and coronary heart disease risk, these interactions did not maintain statistical significance after adjusting for multiple comparisons. Altogether, these findings emphasize the independent importance of sleep for cardiovascular health and mortality, while suggesting that future sleep research should incorporate prospective assessments of caffeine exposure.