Since the introduction of folic acid fortification of flour 10 y ago, an initiative to consider fortifying flour with vitamin B-12 has gained momentum in the United States. The impetus for this move stems from several considerations, including some evidence that a proportion of neural tube defect pregnancies may be the result of vitamin B-12 rather than folate deficiency. However, no interventional trials have taken place to show the efficacy of vitamin B-12 supplementation or fortification in the primary prevention or recurrence of neural tube defect pregnancies, as was the case with folic acid. Other reasons put forward for the institution of vitamin B-12 fortification include the high prevalence of vitamin B-12 deficiency in certain demographic groups, including the elderly and the young in some countries. Much of this deficiency, however, is subclinical and not associated with manifest morbidity. Moreover, individuals affected by the most severe cases of vitamin B-12 deficiency that are associated with morbidity would not benefit from the concentrations of vitamin B-12 fortification that are practical or that are being considered, because such individuals suffer from malabsorption of vitamin B-12 rather than from an inadequacy of intake of the vitamin. In addition to the well-recognized complications of vitamin B-12 deficiency, such as macrocytic anemia and neurological complications affecting sensory and motor function, more subtle effects have also been described, including osteopenia, neurocognitive impairment, and increased vascular disease risk associated with elevated homocysteine. This analysis focuses on the research questions that are pertinent to the consideration of whether or not to introduce mandatory vitamin B-12 fortification in the United States.