The aim of the present study was to investigate the impact of perceived stress and self-esteem on work-related stress and depression. Two hundred and eighty-four Korean nurses participated in the study. The participants completed four questionnaires, including the Korean short version of the occupational stress scale, the perceived stress scale, the Rosenberg self-esteem scale and the Beck depression inventory. Structural equation modelling was used to determine the relationships among work-related stress, perceived stress, self-esteem, and depression. Work-related stress was positively associated with depression. Perceived stress was inversely related to self-esteem and positively associated with work-related stress and depression, respectively. Self-esteem was negatively associated with work-related stress and depression. Structural equation modelling revealed that self-esteem and perceived stress fully mediate the relationship between work-related stress and depression. Future studies should further investigate the effect of psychological characteristics on work-related stress and symptoms of depression. Copyright © 2012 John Wiley & Sons, Ltd.