Mitigation of irradiation injury to salivary glands was previously reported using a cell-free extract from mouse bone marrow. However, to bring this potential therapy a step closer to clinical application, a human bone marrow cell extract (BMCE) needs to be tested. Here, we report that irradiation-induced injury of salivary glands in immunocompetent mice treated with human BMCE secreted 50% more saliva than saline-injected mice, and BMCE did not cause additional acute inflammatory reaction. In addition, to identify the cell fraction in BMCE with the most therapeutic activity, we sorted human bone marrow into 3 cell fractions (mononuclear, granulocyte, and red blood cells) and tested their respective cell extracts. We identified that the mononuclear cell extract (MCE) provided the best therapeutic efficacy. It increased salivary flow 50% to 73% for 16 wk, preserved salivary parenchymal and stromal cells, and doubled cell proliferation rates while producing less inflammatory response. In contrast, the cell extract of granulocytes was of shorter efficacy and induced an acute inflammatory response, while that from red blood cells was not therapeutically effective for salivary function. Several proangiogenic (MMP-8, MMP-9, VEGF, uPA) and antiangiogenic factors (TSP-1, PF4, TIMP-1, PAI-1) were identified in MCE. Added advantages of BMCE and MCE for potential clinical use were that cell extracts from both male and female donors were comparably bioactive and that cell extracts could be stored and transported much more conveniently than cells. These findings suggest human BMCE, specifically the MCE fraction, is a promising therapy against irradiation-induced salivary hypofunction.