To review the evidence for an expanded approach to identifying and treating patients with cobalamin deficiency. Controversy surrounds this issue. Some authors claim that seven times more patients are treated than have true deficiency. New diagnostic tests and identification of patients who have neurologic consequences without hematologic abnormalities suggest that some of these patients have a vitamin B12 tissue deficiency.A MEDLINE search of English-language literature from 1990 to 1995 revealed retrospective and prospective studies of diagnostic tests; prospective surveys; a cohort study; and retrospective and prospective case series, some with control groups. No double-blind controlled trials of treatment were found.Some patients with neuropsychiatric abnormalities develop a cobalamin tissue deficiency that can be detected by elevated serum homocysteine and methylmalonic acid levels despite normal serum vitamin B12 levels without macrocytic anemia. Serum cobalamin testing is neither sensitive nor specific in the low normal range for cobalamin deficiency. Treatment recommendations vary because no controlled trials support any recommendations. Oral cobalamin is an underused alternative to parenteral treatment.Until the newer diagnostic tests become widely available, family physicians must continue to take a traditional approach to diagnosing vitamin B12 deficiency. There is, however, support for a clinical trial of treatment in patients with neuropsychiatric symptoms.