The role of psychological distress in the onset and progression of prostate cancer is an under-researched area. We report results from a cohort study in which we have examined the relationship between indices of psychological distress and prostate specific antigen (PSA) levels (a glycoprotein associated with prostatic diseases including cancer) in men with and without prostate cancer and also the relationship between distress and the likelihood of receiving a diagnosis of prostate cancer. Data were obtained from 4886 men who attended PSA testing and biopsy as part of the ProtecT (Prostate testing for cancer and treatment) study (mean age 62years; 98.9% White). Men completed questionnaires measuring anxiety, depression and urinary symptoms at initial PSA testing and again at biopsy when PSA was re-measured. Regardless of the subsequent diagnosis, there was no association between psychological distress scores at initial PSA testing and PSA measured at biopsy. However, analyses pertaining to the relationship between distress and cancer diagnosis showed that men with 'possible' clinical depression at initial PSA testing (n=519/4886) were 23% more likely to have a diagnosis of prostate cancer. These analyses highlight the need for further investigations into the possible role of depressed mood in the onset of prostate cancer and, in particular, research examining the biological basis for these relationships.