The comparative strength of the 5-HTTLPR polymorphism as a 'predictor' of depression after major stress, versus the 'protective' effect of psychological resilience (PR) against depression after major stress, was tested in a homogeneous sample of older men who had all received a diagnosis and treatment for prostate cancer. Results supported the association between PR and lower depression after stress, but did not support the association between the 5-HTTLPR and elevated depression after stress. Examination of PR at scale, factor, and item level identified the specific PR-related behaviour that was the most powerful predictor of low depression. These data suggest that the carriage of the short form of the 5-HTTLPR may negate the protective effect of PR against depression in these men, or that PR may nullify the depression vulnerability of this form of the 5-HTTLPR. These findings may explain some of the 'null' findings regarding the link between the 5-HTTLPR and depression in the wider literature by arguing for an interaction between these two factors in the association between major stress and depression.