Shoulder pain is common in the working population and causes loss of productivity, high economic costs, and long absences. Simultaneous evaluation of the complex relationships between work organization (e.g., work pace, application of quality standards), psychosocial and physical risk factors, stress, and shoulder pain is rare. The aim of this study was to explore the direct and indirect relationships between workplace risk factors, perceived stress, and occurrence of shoulder pain in workers of the Cohorte des Salaries Ligeriens study. A total of 3,710 workers in a French region were randomly selected for inclusion between 2002 and 2005. They completed a self-administered questionnaire about musculoskeletal symptoms, individual factors, and exposure to work constraints. In 2007, they responded to a follow-up questionnaire. The study sample comprised 1,400 workers free of shoulder pain at baseline. Structural equation models were used. For both sexes, exposure to factors related to work organization had an effect on physical and psychosocial risk factors. Psychological demand was the only psychosocial constraint that increased perceived stress. Shoulder pain was influenced directly by physical risk factors for both sexes and by perceived stress for men. In view of their distal action, work organization is an important target for strategies to prevent shoulder pain in the working population.