Background: Sex chromosome loss (SCL) has long been deemed a physiological age-related phenomenon, but due to its increasingly common appearance in pathogenic settings, there has been renewed debate as to its clinical significance. In hematologic patients receiving sex-mismatched bone marrow transplantations (BMT), depending on the donor/patient sex combination, the appearance and/or disappearance of the Y chromosome can have various implications such as engraftment, relapse, or even donor cell leukemia. This diversity, especially when coupled with deletion/duplication of an X chromosome, can be extremely misleading when determining post-BMT chimerism and may even cause misdiagnosis. We investigated the incidence and clinical implications of SCL in patients who received sex-mismatched BMT. Methods: The present study includes 476 patients (262 females and 214 males) that underwent sex-mismatched BMT over a 10-year period (2005-2015) at Seoul National University Hospital. Retrospective review of electronic medical records was performed to obtain relevant clinical data. SCL was determined by X/Y Fluoresence in situ Hybridization (FISH) and its clinical significance was evaluated in conjunction with other available cytogenetic (karyotyping, FISH), molecular (short-tandem repeat (STR) analysis), and bone marrow (BM) aspiration/biopsy results. Correlation between clinical factors were analyzed via Kendall's rank correlation coefficients. Kaplan-Meier survival analysis was utilized to obtain and compare survival curves of the patients according to age, sex, recipient STR percentage, SCL percentage, and post-BMT time interval till appearance of SCL. Two types of survival was analyzed: the first being the survival from initiation of BMT, and the second being the survival from the onset of SCL. Results: From a total of 476 patients who received sex-mismatched BMT, 77 patients (16.2%) showed post-BMT SCL. Interestingly, the number of female recipients with SCL was significantly higher than males (67 vs 10), but the overall degree of SCL (%) was higher in male patients. Acute myeloid leukemia (AML) was the most common primary diagnoses in all patients, but the distribution of diagnoses was not different between sexes. Females had a lower average age compared to males (33.8 vs 50.9 years). Correlation analysis showed that SCL positively correlated with both STR and age, however, there were a few cases with discrepancies between the SCL percentage and recipient STR percentage. These discrepancies usually occurred at low SCL and STR percentages (32 years (p=0.003, Figure 1 a), males (p8.25% (p3.8% (p = 0.006, Figure 1 d), and time interval from BMT to onset of SCL ≤10.9 months (p = 0.002, Figure 1 e). Comprehensive analyses of X/Y FISH combined with aberrant FISH markers, G-banding, and BM blast counts confirmed both higher relapse and mortality rates in SCL patients. Conclusions: Vigilance is required when interpreting X/Y FISH results, especially when relatively low percentages ( Disclosures No relevant conflicts of interest to declare.