PURPOSE: The association between weight change across adulthood and obstructive sleep apnea (OSA) is unclear. This study aimed to evaluate the effect of weight change across adulthood on OSA and subsequent mortality. METHODS: This study included 2019 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Weight at ages 20 and 40 was recalled at Exam 1, and height and weight were measured in Exam 5 and used to calculate current body mass index (BMI). Home-based polysomnography was conducted for each enrolled participants in the MESA Sleep Study immediately following Exam 5. The relationship between changes in BMI across adulthood and the risk of OSA was investigated using logistic regression and restricted cubic splines. In addition, the association between BMI change and all-cause mortality was examined using Cox regression. RESULTS: Of 2019 participants (median age: 67 years; 930 [46.1%] men), 970 (48.0%) had OSA. Compared to the non-OSA group, participants in the OSA group were older, more often male, and had greater weight changes across adulthood. Logistic regression showed that increased BMI across adulthood was an independent risk factor for OSA. Further studies showed that both mild (0–10%) and significant (>10%) increases in BMI between the ages of 20 and 40 were associated with a higher risk of OSA, and this finding remained after adjustment for current BMI. Subgroup analyses showed consistent results for participants with current BMI <30 or ≥30. In addition, weight gain from age 20 to 40 was also associated with an increased mortality risk after OSA diagnosis. CONCLUSION: Weight gain in early adulthood was associated with a higher risk of OSA and subsequent mortality, regardless of weight status in later life. Therefore, maintaining a normal body weight in early adulthood should be actively promoted to prevent OSA and improve prognosis.