Patients with chronic fatigue syndrome (CFS) often experience depression which may negatively affect prognosis and treatment outcome. Research has shown that depression in CFS is associated with maladaptive or self-critical perfectionism. However, currently, little is known about factors that may explain this relationship, but studies in nonclinical samples suggest that low self-esteem may be an important mediator of this relationship. The present study therefore examined whether self-esteem mediated the cross-sectional association between maladaptive perfectionism and severity of depression in 192 patients meeting Centres for Disease Control and Prevention criteria for CFS. Patients completed self-report measures of maladaptive perfectionism, self-esteem, depression, and fatigue. Regression analyses and more direct tests of indirect effects (i.e., the Sobel test and bootstrapping) were used to test for mediation. Congruent with expectations, we found that self-esteem fully mediated the relationship between maladaptive perfectionism and depression in CFS. Findings from this study suggest that self-esteem may explain the link between maladaptive perfectionism and depression in CFS, which may have important implications for the treatment and prevention of depression in these patients.