OBJECTIVES: To examine the effects of physical work environment on long term sickness absence and to investigate interaction between physical and psychosocial risk factors. DESIGN AND SETTING: Prospective cohort study of long term sickness absence among employees in Denmark. PARTICIPANTS: 5357 employees interviewed in 2000 about their physical work environment, and various covariates were followed for 18 months in a national sickness absence register. Outcome measurements Cox regression analysis was performed to assess risk estimates for physical risk factors in the work environment and onset of long term sickness absence, defined as receiving sickness absence compensation for eight consecutive weeks or more. RESULTS: 348 participants (6.9%) developed long term sickness absence during follow-up. Of these, 194 (55.7%) were women and 154 (44.3%) were men. For both female and male employees, risk of onset of long term sickness absence was increased by extreme bending or twisting of the neck or back, working mainly standing or squatting, lifting or carrying loads, and pushing or pulling loads. Significant interactions were found for three combinations of physical and psychosocial work environment risk factors among female employees (P<0.05). CONCLUSION: Uncomfortable working positions, lifting or carrying loads, and pushing or pulling loads increased the risk of onset of long term sickness absence. The study shows a potential for reducing long term sickness absence through modifying work postures straining the neck and back, reducing the risk of work done standing or walking, and reducing the risk associated with handling loads. Dealing with psychosocial stressors simultaneously may improve physical intervention efforts further for female employees.