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Continuous-flow left ventricular assist devices (LVADs) subject elements of the blood to significant stress, resulting in clinically significant and subclinical hemolysis. We sought to prospectively determine whether baseline red-cell osmotic fragility of an advanced heart-failure patient influences the hemolytic response to LVAD support. Osmotic fragility assesses the degree of red-blood-cell hemolysis under varying degrees of osmotic stress. Assays were prospectively obtained on 50 consecutive patients prior to placement of continuous-flow LVADs: HeartMate II (n = 34), Jarvik 2000 (n = 5), HeartWare (n = 6). The mean age of the patients was 60.2 years and 87% were male and 47% were nonischemic. The overall median post-LVAD lactate dehydrogenase (LDH) was 583 (427–965), and there was no difference between devices. Mean hemolysis was 15.68 ± 12.96% at 0.45% NaCl (the inflection point of the osmotic fragility hemolysis curve). A scatter plot did not reveal any relationship between preoperative osmotic fragility and postoperative LDH. Linear regression confirmed no predictive relationship (p = 0.71). In conclusion, preoperative variations in osmotic fragility do not appear to account for differences in hemolysis following ventricular assist device placement. Mechanical forces generated by existing LVADs result in similar levels of biochemical hemolysis, as assessed by LDH, despite baseline differences in a patient’s osmotic red-cell fragility.