Few studies have analysed the association between the organisational work environment and depression in hospital workers and we still have little understanding of how processes in the practice environment are related to depressive disorders. However, individual perception of an imbalance between efforts made and expected rewards has been associated with incident depression. The main goal of this study was to test the hypothesis that some organisational constraints at the work-unit level may be related to depressive symptoms in hospital workers, either directly or through individual perceptions of effort–reward imbalance (ERI). In 2006, 3316 female registered nurses and nursing aids working in 190 work units in seven French university hospitals, recruited from the baseline screening of an epidemiological cohort study (the ORSOSA study), responded in 2006 to valid self-report questionnaires (CES-D, ERI). The organisational work environment was assessed with the self-rated Nursing Work Index – Extended Organisation (NWI-EO) aggregated at the work unit level. Multilevel models were used. We found that poor relations between workers within work units were associated with higher CES-D score, independently of perceived ERI. Low level of communication between workers in the unit was associated with individual perceptions of ERI and indirectly associated with depressive symptoms. Understaffing and non-respect of planned days off and vacations were associated with perceived ERI but these organisational constraints were not associated with depressive symptoms. Our study allowed us to identify and quantify organisational factors that have a direct effect on hospital workers’ depressive symptoms, or an indirect effect through perceived ERI. Better understanding of the effect of organisational factors on health through perceived ERI would provide targets for successful interventions. Organisational approaches may be more effective in improving mental health at work and may also have a longer-lasting impact than individual approaches.