Objectives To examine the relationship between erythrocyte mean corpuscular volume (MCV) and cognitive performance over time. Design Longitudinal. Setting Sample from the Baltimore Longitudinal Study of Aging (BLSA). Participants Eight hundred twenty-seven participants from the BLSA (mean age 67, range 5096). Measurements Mean corpuscular volume and several other blood indices were measured, including hemoglobin, iron, ferritin, vitamin B12, folate, white blood cell count, albumin, and erythrocyte sedimentation rate. Cognitive performance was examined using neuropsychological measures of visual memory, verbal memory, language, attention, executive function, and global mental status. Results High MCV levels were significantly associated with lower global mental status even after adjusting for potential confounders. High MCV levels were also significantly associated with high rates of decline on tasks of global mental status, long delay memory, and attention, even after adjusting for potential confounders. Conclusion The findings confirm a previous observation that larger erythrocytes in older adults are associated with poorer cognitive function. Anemia and inflammation do not appear to explain the relationship between MCV and cognition. Further research is needed to clarify the mechanisms behind this association. J Am Geriatr Soc 61:84-89, 2013.