In this study, we performed weekly assessment of morphology-related parameters through monitoring of CPD-SAGM leuco-filtered erythrocyte concentrates from blood withdrawal until the 42nd day of storage. Liquid storage of red blood cells (RBCs) delivers a blood-derived therapeutic, which is safe, available, effective and affordable for most patients who need transfusion therapy in developed countries. However, a growing body of accumulating controversial evidences, from either biochemical or retrospective clinical studies, prompted safety concerns about longer stored RBCs. Statistical image analysis through scanning electron microscope was coupled to osmotic fragility and erythrocyte sedimentation rate. We could observe that by day 21 more than 50% of RBCs displayed non-discocyte phenotypes. This observation was related to an increase in osmotic fragility, which was totally overlapped in day 0 controls and day 7 RBCs while only slightly augmented in day 14 samples. Cation dysregulation (pH internal/external alteration and potassium) might both reflect and trigger a negative feedback loop with metabolic fluxes and membrane cation pumps. Morphology parameters suggest that significant alterations to RBC morphology over storage duration occur soon after the 14th day of storage, as to become significant enough within the 21st day. © 2012 The Authors. Transfusion Medicine © 2012 British Blood Transfusion Society.