Introduction: The classical response to stress is a time dependent phenomenon. Surgical interventions following traumatic injury often act as a “second hit” and contribute to poor patient outcomes. Stress conditioning protocols have demonstrated the potential to provide clinically useful cytoprotection to humans prior to invasive surgical procedures. Future clinical applications will require a simple assay that will reflect an individual’s global resistance to stressful threats. The red blood cell (RBC) is susceptible to lysis by osmotic stress and can be easily quantitated. We tested the hypothesis that RBC resistance to osmotic lysis would increase following exposure to classical heat shock temperatures. Methods: In accordance with guidelines set by the Animal Care and Use Committee, female Lewis rats (200gm) received whole-body hyperthermic stress (n=3, WBH, 42-43C° for 15 min.), sham hyperthermic stress (n=5, SHAM, 37-38C° for 15 min.) or no stress (n=4) 8-10 hours prior to having venous blood sampled and exposed to graded hypotonic saline solutions (0.2, 0.15, 0.10, 0.05 % NaCl). Red cell lysis was determined by measuring the hemoglobin in solution using standard spectrophotometry techniques (OD642). All specimens were tested in triplicate. Specimen lysis was standardized as a percentage of lysis observed in distilled water (100% lysis) for each sample. Percentage lysis was then compared between groups. Next, resistance to osmotic stress was characterized in healthy volunteers and patients residing in a trauma-general surgical ICU. The human study was approved by our Institutional Review Committee. Results: Rodent: Red cell lysis was significantly reduced in WBH group at all degrees of hypotonicity as compared to both SHAM and no stress groups. For example, mean percent lysis at 0.1% saline was 16±2% for WBH group vs 38±4% and 34±4% for the SHAM and no stress groups respectively, p <0.05. Human: Mean RBC lysis, at 0.35% saline, was significantly less in healthy volunteers (n=13) 78 ±24% compared to the ICU patients (n=43) 95±8%, p<0.001. Conclusion: RBC-osmotic lysis may provide a simple clinical tool to measure an individual’s resistance to stressful events seen within the context of intensive medical and surgical care. Initial clinical work suggests that trauma and surgical ICU patients may have a reduced resistance to stressful events based on the RBC-lysis assay reported here.