To the Editor: In their recent article in Clinical Chemistry (1), Valente and colleagues advocate that holotranscobalamin II (holoTC)1 become the primary diagnostic test of vitamin B12 status. I believe that study flaws undercut the authors' recommendation. Moreover, the validation difficulties extend to deeper, more basic issues that continue to limit translation of the holoTC concept, despite its theoretical attractiveness. Validation efforts have typically compared holoTC against serum B12 in general populations and have used imperfect tools with often-arbitrary cutpoints to define B12 status. Such approaches and their reliance on methylmalonic acid (MMA), despite its questionable diagnostic specificity, have been critiqued (2). Valente et al. reuse this model with just 1 modification, the substitution of erythrocyte vitamin B12 (RBC-B12) for MMA as the arbiter of B12 status. That innovation misfires, however, because RBC-B12 is probably an even poorer standard than MMA. No convincing data anywhere, including the references cited by Valente and colleagues, justify the report's assumption that RBC-B12 represents tissue B12 status. Very little is known about what RBC-B12 concentrations really mean. The measurement of RBC-B12 has been deemed insufficiently informative …