There are many genetic and acquired risk factors that are known to cause venous thromboembolic disorders (VTE). One of these is the Prothrombin G20210A mutation, which has been identified in 1996. Prothrombin G20210A mutation causes higher levels of the clotting factor prothrombin in the blood of carriers, which creates a higher tendency towards blood clotting (hypercoagulability), and therefore the carriers become at higher risk of developing VTE. High prevalence of Prothrombin G20210A mutation was reported in Caucasian populations, but the prevalence was almost absent in non-Caucasians. That was most obvious in countries of South Europe and the Mediterranean region. This review article discusses Prothrombin G20210A mutation, how it causes VTE, the origin of the mutation, and its distribution worldwide with special concentration on the Mediterranean area.