OBJECTIVE:To review recent evidence that suggests vitamin B12 is associated with risk reduction for some chronic diseases and birth defects. QUALITY OF EVIDENCE:A MEDLINE search from 1999 to 2007 was performed using the key word vitamin B12. The most relevant articles (129) dealt with cardiovascular disease, cancer, mental health, and birth outcomes;most studies presented level II evidence. MAIN MESSAGE:Vitamin B12 might confer health benefits; however, such benefits are difficult to ascertain because of the complementary functions of vitamin B12 and folic acid. Vitamin B12 might lower high homocysteine levels below a threshold level achieved by folic acid alone. Furthermore, the interactions between the nutritional environment and genotype might have an important influence on vitamin B12, chronic disease risk, and risk of neural tube defects. CONCLUSION:Vitamin B12 might help protect against chronic disease and neural tube defects, but more research, particularly in the area of nutritional genomics, is needed to determine how vitamin B12 might augment the benefits of folic acid. Some consideration should be given to the potential value of fortifying foods with vitamin B12 in addition to the current mandatory folic acid fortification of grains.