BACKGROUND: Epidemiological studies have linked psychological stress with an increased risk of breast cancer, however few studies have linked stress hormone signalling to cancer initiation mechanistically. This may be particularly pertinent in populations already at risk due to mutations in the cancer predisposition genes BRCA1/2. METHODS: Here we employ BRCA1/2 knockdown in breast and prostate epithelial cells to examine the effects of the stress hormone cortisol on DNA damage and repair. We perform a retrospective analysis of plasma cortisol and urinary 8-OHdG in a female BRCA-mutation carriers cohort (n = 62) and validate our findings in a male cohort (n = 70). RESULTS: Cortisol promotes DNA damage in normal mammary epithelial cells, and in a BRCA-deficient setting, delays DNA repair. In female BRCA-mutation carriers higher plasma cortisol levels are associated with an increased risk of cancer. In a male BRCA-mutation cohort risk of prostate cancer was also significantly increased in those with higher cortisol levels. Urinary 8-OHdG, a biomarker of oxidative DNA damage, was also correlated with a risk of breast cancer and prostate cancer. CONCLUSION: Taken together these findings demonstrate that psychological stress, through the induction of DNA damage by cortisol, may increase the cumulative risk of cancer in BRCA-mutation carriers.