Diagnosis of cobalamin deficiency can be difficult due to the variation in clinical presentation and lack of specificity of the laboratory findings. Although hypersegmentation and macrocytosis are important findings observed in cobalamin deficiency they are not sensitive and spesific. Additionally, cobalamin assays in commercial laboratories, being not reliable, makes the diagnosis more difficult. The metabolite assays, such as the total homocysteine and methylmalonic acid are costly, which restricts their widespread routine use. Our aim was to find out problems in diagnosis of cobalamin deficiency in general practice, and establish a better and cost-effective decision strategy for the diagnosis of this common clinical entity. Fifty patients with the diagnosis of cobalamin deficiency were retrospectively evaluated with respect to diagnosis. Normal cobalamin levels were observed at presentation in eight (16%) patients. Reticulocyte crisis was observed in all patients on the seventh day of cobalamin replacement therapy and all hematological parameters returned to normal at the end of three months of treatment. In anemic patients with clinical and biochemical findings suggestive of megaloblastic anemia, even though serum cobalamin level is normal, a therapeutic trial of cobalamin is cost effective and prevents delay in diagnosis.