BACKGROUND Although females have a lower baseline hemoglobin (Hb) compared to males, it is unknown whether females have a greater tolerance for anemia when hospitalized. We tested the hypothesis that females tolerate severe anemia better than males, with decreased inpatient mortality in this setting. STUDY DESIGN AND METHODS We conducted a retrospective cohort study in 230,644 adult patients admitted to Johns Hopkins Hospital from January 2009 to June 2016. The relationships between nadir Hb and percentage change in Hb with inpatient mortality were assessed for nontransfused males and females. A multivariable logistic regression was used to determine risk‐adjusted differences between males and females for the likelihood of inpatient mortality at nadir Hb levels of 5, 6, and 7 g/dL. RESULTS Males had increased mortality when nadir Hb was 6.0 g/dL or less (p < 0.05), whereas females did not. The risk‐adjusted likelihood for inpatient mortality was greater for males compared to females at a nadir Hb of 6 g/dL or less (odds ratio, 1.84; 95% confidence interval, 1.09‐3.16) (p = 0.02), but this sex‐related difference was not significant at a nadir Hb of 5 or 7 g/dL or less. Inpatient mortality increased significantly in both males and females when the percentage decrease in Hb was greater than 50% from baseline (p < 0.05). CONCLUSIONS Compared to males, females tolerate a lower nadir Hb, but a similar percentage change in Hb, before an increase in inpatient mortality is recognized. The findings suggest that females may be “preconditioned” to tolerate anemia better than males.