This cross-sectional study of 267 hospital workers from different professions tested the hypothesis that affective stress responses mediate the effects of the psychosocial work environment on musculoskeletal complaints (MSCs). Self-reported psychosocial conditions,ergonomic workloads, affective stress and energy responses, and MSCs were analysed with a series of logistic regression analyses. The psychosocial variables were strongly related to stress and energy, and stress was related to MSCs. Neck and shoulder complaints were more common in the group with high demands and low skill discretion. This was the only significant relation between psychosocial variables and MSCs that was not explained by their confounding with ergonomic workload. However, controlling for stress did not substantially reduce or reduce this interaction effect, which would have been the case if it had been mediated (completely or partially) by stress.