We report the observation of a high neutrophil myeloperoxidase activity (MPXI) in patients with megaloblastic anemia. MPXI is rapidly measured as part of an automated complete blood count (Technicon H*1, Technicon Instruments Corp, Tarrytown NY). We describe the range of MPXI levels in healthy and patient populations and in 10 cases of megaloblastic anemia, including five having elevated mean cell volume (MCV) and five without macrocytosis. Regardless of the MCV, our megaloblastic patients had hypersegmented neutrophils and elevated MPXI levels without visible alteration of granule content. MPXI measurement may be particularly useful in identifying cases of “masked megaloblastic anemia” where the MCV is below 100 fL. The advantage of the MPXI over other methods of uncovering masked megaloblastic anemia is its simplicity when performed as part of a routine complete blood count on an automated hematology instrument.