Abstract Introduction Irregularly timed sleep, inconsistent duration, and non-optimal sleep duration have been implicated in the etiology of cardiovascular disease and premature mortality. These dimensions of sleep map behaviorally to regular bed and wake times. Our aim was to estimate the association of regular sleep of optimal sleep duration with all-cause mortality in a diverse US sample. Methods We used data from the Multi-Ethnic Study of Atherosclerosis Sleep Study (2010-2013) at Exam 5. Sleep was measured by 7-day wrist actigraphy, concurrent with at-home polysomnography and validated sleep questionnaires. We used K-means clustering on wrist-actigraphy regularity and duration data to assign individuals to categories of ‘regular-optimal’ or ‘irregular-insufficient’ sleep, labels describing sleep tendencies in each group. Using proportional hazard models with multi-variate adjustment for socio-demographics (age, female sex, race/ethnicity, marital status, and day vs non-day work schedules), lifestyle (moderate-vigorous physical activity, smoke status), health status (depressive symptoms, body mass index, total medications, prevalent cardiovascular disease), and measures of major sleep disorders (the Apnea-Hypopnea Index, insomnia severity, restless legs), we estimated all-cause mortality associations with sleep patterns. Sensitivity analyses additionally adjusted or, via propensity scores, matched on income, education, prevalent chronic lung disease, prevalent cancer, hypertension, diabetes, and diet. Results Among 1,726 participants who were followed for a median of 7.0 years (Q1-Q3, 6.4-7.4 years,) there were 171 deaths. The ‘regular-optimal’ group had 42% lower mortality risk compared to the ‘irregular-insufficient’ sleep group (Hazard Ratio [95% Confidence Interval]: 0.58 [0.43, 0.80]), in the fully adjusted model and was robust to sensitivity analyses. Conclusion Individuals characterized by a sleep pattern of ‘regular and optimal’ duration sleep had significantly lower mortality compared to those with an ‘irregular and less sufficient’ sleep pattern. The regular and optimal duration phenotype maps behaviorally to regular bed and wake times, suggesting potential health benefits of adherence to recommended sleep practices. Support (if any) JC was supported by the American Academy of Sleep Medicine’s Foundation Grant: 269-FP-22 This work was also supported by the following National Institute of Health (NIH) grants: 5T32HL007901-19, 5K01HL138211-05, K01HL143034, R01HL098433. SR was partly funded by the NIH National Heart, Lung, and Blood Institute (NHLBI) R35HL135818.