A polymorphism of the gene encoding the extra-large stimulatory G-protein alpha-subunit (XLalphas), originally identified in three patients with a bleeding tendency, involved a 36-bp insertion and two missense changes. A paternally-inherited insertion displayed a moderate platelet Gsalpha over-expression, which lead to platelet hypo-reactivity. These data prompted us to investigate the genetic, functional and clinical relevance of this polymorphism in the Mediterranean population. We included 414 healthy subjects and three case/control studies: 263 consecutive patients with a first episode of primary intracerebral haemorrhage, 195 patients with deep venous thrombosis, and 104 patients with cerebrovascular disease. Controls were selected by approximating criteria to match selected risk factors to patients. Moreover, we performed studies of platelet function. We developed a simple method to determine the methylated allele, by digestion of genomic DNA with Sma I before polymerase chain reaction amplification. We identified two new rare variants, resulting from the loss of repeat units 7 and 5. The AB genotype was present in 3.6% of healthy population and the prevalence of the B allele was similar among cases and controls. Accordingly, the non-methylated B allele did not modify either the expression of platelet Gsalpha or the platelet response to Gs-agonists. Thus, our study suggests a minor functional role of XLalphas polymorphism in thrombotic or in haemorrhagic disorders.