Study Objective: To examine the effects of obesity and frequent mental distress (FMD) on the relationship of sleep duration with coronary heart disease (CHD), stroke, and diabetes. Design: Cross-sectional study. Setting: Population-based surveillance. Participants: There were 54,269 adults age 45 y or older who completed the 2010 Behavioral Risk Factor Surveillance System survey in 14 states. Results: Nearly one third (31.1% or an estimated 11.1 million) of respondents age 45 y and older reported being short sleepers (<= 6 h), 64.8% being optimal sleepers (7-9 h), and 4.1% being long sleepers (>= 10 h) in a 24-h period. Compared with the optimal sleep duration, both short and long sleep durations were significantly associated with obesity, FMD (mental health was not good >= 14 days during the past 30 days), CHD, stroke, and diabetes after controlling for sex, age, race/ethnicity, and education. The U-shaped relationships of sleep duration with CHD, stroke, and diabetes were moderately attenuated by FMD. The relationship between sleep duration and diabetes was slightly attenuated by obesity. Conclusions: Sleep duration had U-shaped relationships with leading chronic diseases. Further prospective studies are needed to determine how mental health and maintenance of a normal weight may interact with sleep duration to prevent chronic diseases.