Acute lymphoblastic leukemia (ALL) is a proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. Risk stratification of ALL is based on age, white blood cell count, early therapeutic response, and minimal residual disease (MRD) which are found to play a role both in ALL prognosis and relapse prediction. Relapse remains a major obstacle to achieving a 100% overall survival rate, and relapsed B-ALL continues to be the leading cause of cancer-related death. CD81 is an integral surface membrane protein that is involved in signal transduction in B cells, but its biological role in ALL is not well characterized. Relapse often results from the development  chemoresistance. One of the mechanisms of chemoresistance involves ALL cell interactions with the bone marrow microenvironment. This is known as BM microenvironment induced chemoprotection , which is done by members of the tetraspanins family, mainly CD81 which are known to mediate microenvironmental interactions. Flow cytometry (FC) is a rapid, convenient, and generally applicable technique for detecting (MRD), it can differentiate leukemic cells from their normal immature Blineage counterparts, which are termed hematogones which are major obstacles in MRD detection, The ideal FC marker for detecting MRD in ALL should show a consistent pattern of expression in hematogones and an aberrant expression pattern in leukemic cells. and minimal overlap in expression between benign and leukemic cells, and its level of expression in leukemic cells should be stable over time .CD81 expression is aberrantly dim in a small series of ALL cases and this suggests the possible usefulness of CD81 expression in distinguishing ALL cells from hematogones, so it can be used as a minimal residual disease marker.