Objectives: The objectives of this study are to investigate the relation between obesity and labour force exit via diagnosis-specific disability benefits, and whether physical workload modifies this association. Methods: A longitudinal analysis was performed among 3 28 743 Swedish construction workers in the age of 15-65 years. Body weight and height were measured at a health examination and enriched with register information on disability benefits up to 37 years later. Diagnoses of disability benefits were categorised into cardiovascular diseases (CVDs), musculoskeletal diseases (MSDs), mental disorders and others. A job exposure matrix, based on self-reported lifting of heavy loads and working in bent forward or twisted position, was applied as a measure of physical workload. Cox proportional hazards regression analyses were performed, and the relative excess risk due to interaction (RERI) between obesity and physical workload was calculated. Results: Obese construction workers were at increased risk of receiving disability benefits (HR 1.70, 95% CI 1.65 to 2.76), mainly through CVD (HR 2.30) and MSD (HR 1.71). Construction workers with a high physical workload were also more likely to receive a disability benefit (HR 2.28, 95% CI 2.21 to 2.34), particularly via MSD (HR 3.02). Obesity in combination with a higher physical workload increased the risk of disability benefits (RERI 0.28) more than the sum of the risks of obesity and higher physical workload, particularly for MSD (RERI 0.44). Conclusions: Obesity and a high physical workload are risk factors for disability benefit. Furthermore, these factors are synergistic risk factors for labour force exit via disability benefit through MSD. Comprehensive programmes that target health promotion to prevent obesity and ergonomic interventions to reduce physical workload are important to facilitate sustained employment.