Objective To investigate the effect of chronic stress as measured in cortisol concentrations upon the association between psychological resilience (PR) and depression in prostate cancer (PCa) patients. Methods A total of 104 men with PCa completed inventories on PR, depression, and background factors, plus gave a sample of their saliva for cortisol assay. Results The inverse correlation between PR and depression was present only for PCa patients with low or moderate concentrations of salivary cortisol (when classified as more than 1.0 SD below the mean vs within 1.0 SD of the group mean) but not for those men whose cortisol was >1.0 SD from the group mean. Specific PR factors and behaviours that made the greatest contribution to depression were identified for the low and moderate cortisol groups. Conclusions These results suggest that there are particular aspects of PR that are most strongly related to depression, but that PR's inverse association with depression may be absent in participants with extreme chronic physiological stress.