Background: Obesity and depression are closely linked, and each has been associated with disability. However, few studies have assessed inter-relationships between these conditions. Design and methods: In this study, 4641 women aged 40-65 completed a structured telephone interview including self-reported height and weight, the Patient Health Questionnaire (PHQ) assessment of depression, and the World Health Organization Disability Assessment Schedule II (WHODAS II). The survey response rate was 62%. We used multivariable regression models to assess relationships between obesity, depression, and disability. Results: The mean age was 52 years; 82% were White; and 80% were currently employed. One percent were underweight, 39% normal weight, 27% overweight, and 34% obese. Mild depressive symptoms were present in 23% and moderate-to-severe symptoms were present in 13%. After multivariable adjustment, depression was a strong independent predictor of worse disability in all 7 domains (cognition, mobility, self-care, social interaction, role functioning, household, and work), but obesity was only a significant predictor of greater mobility, role-functioning, household, and work limitations (P < 0.05) (overweight was not significantly associated with any disability domain). Overall, the effect on disability was stronger and more pervasive for depression than obesity, and there was no significant interaction between the two conditions (P > 0.05). Overweight and obesity were associated with 5760 days of absenteeism per 1000 person-years, and depression was associated with 18,240 days of absenteeism per 1000 person-years. Conclusions: The strong relationships between depression, obesity and disability suggest that these conditions should be routinely screened and treated among middle-aged women.