Pregnancy and puerperium raise the risk of thrombotic events, and these risks are likely to be increased in women who are carriers of thrombophilic gene polymorphisms. Prothrombin G20210A variant is reported to be the second most frequent prothrombotic polymorphism in Caucasians. Our aim was to determine the prevalence of this variant in south Indian women and examine its association with cerebral venous and sinus thrombosis occurring during puerperium. We investigated 96 women with puerperal cerebral veno-sinus thrombosis (CVT) and 103 age-matched women with no post-partum complications. We used restriction fragment length polymorphism analysis to identify their genotypes. The prothrombin G20210A variant was not detected in either the CVT patients or the healthy control subjects. Our study on a large series of patients with puerperal CVT shows that the prothrombin G20210A variant is not present in south Indian women and is not associated with puerperal CVT. This study also highlights the fact that there are racial differences in the risk factors for thrombosis, which should be considered when investigating these patients.