Polymorphism of clotting factor V, comprising Arg506Gln substitution in the factor V molecule, commonly known as Factor V Leiden, represents the most common heritable risk factor for thrombotic events in Indo-Europeans and some Semitic nations. Although it is suggested that this mutation is associated with a survival advantage that has facilitated the spread of this polymorphism in the human population, in this paper we argue against such a Darwinian evolutionary mechanism responsible for the high prevalence of FV Leiden in some countries. Instead, we propose that cultural, climatic, and geographic factors played a role. Taking into account the current distribution of FV Leiden polymorphism and the results of recent assessments of pre-historic human DNA, we suggest that actually the origin of FV Leiden mutation did not occur in the Near East, as is widely believed, but rather in a small isolated population of so-called Basal Eurasians, probably in northern Africa. This founder group probably migrated to the Near East during the Younger Dryas, a geological period associated with climate cooling. Here, they mixed with local people; still Factor V Leiden mutation remained very prevalent in this population. The invention of agriculture, which took place approximately 2,000 years later, gave the descendants of Basal Eurasians an enormous advantage over hunter-gatherers, and probably enabled a successful spread of FV Leiden polymorphism to Europe, Central Asia, and towards the Indian subcontinent.