Transient Global Amnesia (TGA) is an enigmatic amnestic syndrome. We conducted a systematic review to investigate the relationship between the conventional cardiovascular risk factors and TGA. MEDLINE, CENTRAL, EMBASE and PsycINFO were comprehensively searched and 23 controlled observational studies were retrieved. The prevalence of hypertension, diabetes mellitus, dyslipidemia and smoking was lower among patients with TGA compared to Transient Ischemic Attack. Regarding the comparison of TGA with healthy individuals, there was strong evidence suggesting a protective effect of diabetes mellitus on TGA and weaker evidence for a protective effect of smoking. Hypertension was associated with TGA only in more severe stages, while dyslipidemia was not related. In view of these findings, a novel pathophysiological hypothesis is proposed, in which the functional interactions of Angiotensin-II type-1 and N-methyl-D-aspartate receptors are of pivotal importance. The whole body of clinical evidence (nature of precipitating events, associations with migraine, gender-based association patterns) was integrated.