Our aim was to corroborate the observed association between the deletion/deletion (DD) genotype of the insertion/deletion polymorphism in the alpha(2B)-adrenoceptor (AR) and increased risk for acute myocardial infarction (AMI), and to study whether this genotype also confers an increased risk for sudden cardiac death (SCD).Vasospasm has been suggested to play a role in AMI. Alpha(2)-AR mediate coronary vasoconstriction in humans, and studies on mice suggest the involvement of the alpha(2)-AR subtype B in vasoconstriction. A deletion variant of the human alpha(2B)-AR has been associated with impaired receptor desensitization in vitro. In a population-based prospective study of 912 middle-aged men, the DD genotype of the alpha(2B)-AR conferred an increased risk for AMI.A series of 700 unselected sudden out-of-hospital deaths of middle-aged white men subjected to medico-legal autopsy was analyzed.Genotype information was obtained for 683 men (DD = 22%, insertion/deletion = 51%, insertion/insertion = 27%). Carriers of the DD genotype had an increased risk for SCD (n = 278, odds ratio [OR] = 2.0, p = 0.01) and fatal AMI (n = 84, OR = 2.1, p = 0.04) compared with the other two genotypes combined. The risks for SCD and fatal AMI were higher in carriers of the DD genotype who died before the age of 55 years (OR = 4.5 and 5.0, p < 0.001 for both).Middle-aged white men carrying the DD genotype of the alpha(2B)-AR have a significantly increased risk for SCD and AMI, especially before the age of 55 years.