This chapter discusses the occurrence and interpretation of very low serum vitamin B12 in the absence of clinical signs of deficiency. It also discusses the significance and potential clinical meaning of very high serum vitamin B12 in the absence of vitamin B12 treatment. In the absence of clinical symptoms, vitamin B12 levels below the detection limit are not rare in the lab. High vitamin B12 concentrations can be more frequent than low ones in samples sent to clinical labs for vitamin B12 testing. The chapter focuses on the three most common conditions associated with high serum vitamin B12: diabetes and renal insufficiency; liver disorders; different malignancies. Concentrations of vitamin B12 and holotranscobalamin are generally higher in patients with diabetes and renal failure compared with healthy subjects. Concentrations of vitamin B12 binding proteins were significantly higher in patients with liver diseases compared with controls. The association between prostate cancer and high vitamin B12 or low homocysteine was significant in older patients.