The renin-angiotensin system (RAS) adversely affects stroke and cardiovascular disease; polymorphisms in genes involved in this system are associated with cardiovascular disease. The aim of the present study was to confirm the genetic risk of these polymorphisms for stroke and cardiovascular events in a cohort study of 515 hypertensive patients in Japan (follow-up period 90.6±30.2 months). The insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE), the M235T amino acid change in angiotensinogen, and the A1166C polymorphism in angiotensin II type 1 receptor were determined by TaqMan PCR. In Kaplan-Meier analyses, the ACE I/D polymorphism was a risk factor for cerebro-cardiovascular events, especially cardiovascular events (P<0.0001), and the M235T mutation was a risk factor for cardiovascular events (P<0.0105). The cumulative rates of cerebro-cardiovascular end points for the ACE polymorphism were 10.6, 16.4 and 42.2% for the II (n=207), ID (n=244) and DD (n=64) genotype carriers, respectively (P<0.0001). Cox's proportional hazard models revealed that the ACE DD genotype was a risk factor for cerebro-cardiovascular and cardiovascular events (after adjusting for common risk factors), anti-hypertensive treatment and RAS inhibition (P<0.0001). Moreover, after adjustment for the common risk factors left ventricular hypertrophy and previous myocardial infarction/stroke, these phenomena were preserved. Thus, the DD genotype of ACE may be a genetic risk factor for cerebro-cardiovascular disease, especially cardiovascular events, in hypertensive patients in Japan.