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During the final stages of erythropoiesis, lineage-restricted progenitors mature over three to five cell divisions, culminating with withdrawal from the cell cycle and the loss of most organelles, including mitochondria and nuclei. Recent genome-wide association studies in human populations have associated several SNPs near or within FBXO7 with erythrocyte phenotypes. Fbxo7 encodes a multi-functional F-box protein known to bind p27 and participate in selective mitophagy. One SNP causes an amino acid substitution (Met115Ile) and is associated with smaller erythrocytes. We find that the less common IIe115 allele of Fbxo7 binds less efficiently to p27, and cells expressing this allele proliferate faster than cells expressing Met115. We show that an erythroleukaemic cell line with reduced Fbxo7 expression fails to stabilize p27 levels, exit the cell cycle, and produce haemoglobin. In addition, mice deficient in Fbxo7 expression are anaemic due to a reduction in erythrocyte numbers, and this is associated with lower p27 levels, increased numbers of late-stage erythroblasts with greater than 2N DNA content, and delayed mitophagy during terminal differentiation. Collectively, these data support an important physiological, cell cycle regulatory role for Fbxo7 during erythropoiesis. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.