Background: Hemochromatosis (HH) is characterized by chronic iron accumulation, leading to deleterious effects to various organ systems. A common approach to managing iron load involves large-volume venesection. Some countries authorize HH venesections to be used in the development of transfusable blood products, although concerns remain regarding suitability. Due to the high oxidative load associated with hyperferritinemia, it has been proposed that HH blood products may be susceptible to mechanical damage. This is particularly relevant given that typical blood product destinations (eg, transfusion, cardiopulmonary bypass) expose blood to supraphysiologic levels of mechanical stress. We sought to explore the mechanical tolerance of red blood cells (RBC) derived from HH venesections to varied magnitudes and durations of sublethal shear stress. Study Design and Methods: Initially, 110 individuals with HH were recruited; to eliminate the effects of comorbidities, only those who were untreated and uncomplicated were included for comparisons with age-matched healthy controls (Con). RBC were exposed to 25 discrete magnitudes (1-64 Pa) and durations (1-64 seconds) of shear stress. Cellular deformability was assessed before, and immediately after, each shear exposure. Results: In the absence of prior shear exposure, RBC deformability of HH was significantly decreased by 11.5%, compared with Con. For both HH and Con, supraphysiologic shear exposure significantly impaired RBC deformability, although the rate and magnitude of deterioration were elevated for HH. Conclusion: Given that blood products are commonly exposed to high-shear environments (eg, during high-volume transfusion), venesections from asymptomatic and untreated individuals with HH appear suboptimal for the development of therapeutic RBCs.