OBJECTIVE To assess the cause-specific mortality unrelated to prostate cancer (PC) itself in patients with screen-and clinically diagnosed PC. PATIENTS AND METHODS The present study was conducted among participants of the European Randomized Study of Screening for Prostate Cancer. Based on consensus of the causes of death committee (CODC), all patients who died from PC were excluded. In the intervention arm, cases were patients with a screen-detected PC, aged 55-74 years, between 1993 and 2001. These cases were matched to two controls in whom no cancer was found after biopsy, and two controls in whom no cancer was suspected after screening. In the control arm, cases were patients with clinically diagnosed PC, aged 55-74 years, between 1993 and 2001. These cases were matched to four controls without PC. Matching was done with respect to date of birth, screening and/or diagnosis. Men were followed up to 31 December 2007. RESULTS No statistically significant difference in overall mortality between cases and controls in the intervention arm was observed: relative risk (RR) 1.26 (95% confidence interval [CI] 0.96-1.65; P = 0.102) and RR 1.13 (95% CI 0.86-1.47; P = 0.381). In the control arm, the overall mortality was statistically significantly higher in cases relative to controls: RR 1.43 (95% CI 1.03-2.00; P = 0.033). This difference was because of an increased risk of dying from neoplasms and disease of the circulatory or respiratory system among cases: RR 1.61 (95% CI 1.12-2.29; P = 0.009). The present study was limited by the relatively small sample size. CONCLUSIONS Increased mortality unrelated to PC itself was observed in men with clinically diagnosed PC, but not in screen-detected PC. The excess mortality in men with clinically diagnosed PC seems to be as a result of a significantly increased risk of dying from neoplasm and disease of the circulatory or respiratory system. Results have to be studied more thoroughly in further clinical trials.