Lead exposure continues to be a significant public health problem. Osteoporosis, inhibition of fracture healing, and cartilage functional impairment have been reported from lead exposure. Mesenchymal stem cells (MSCs) are a bone marrow population of cells with the ability to differentiate into various cell types, particularly osteocytes and chondrocytes. Despite intensive investigation on the effect of lead poisoning on various cell types, there is very little if any report on the effect of lead on MSCs. The aim of this study, therefore, was to investigate the effect of lead acetate on rat bone marrow derived MSCs toxicity and its mechanism by examining the role of pro- and anti-apoptotic proteins in this process. It was revealed that lead acetate could induce cell death in a dose-dependent manner using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium (MTT) assay. Compared to controls, the significant over-expression of pro-apoptotic proteins, including Bax, caspases-9, -3, and p53, with no significant change in anti-apoptotic Bcl(2) protein were obtained in lead-treated cells using western blotting analysis. There was a significant increase in DNA fragmentation in treated MSCs compared to controls using flow-cytometry. Finally, it might be concluded that lead acetate could induce cell toxicity and apoptosis in MSCs, causing instability in mitochondria and in turn activation of the intrinsic pathway including over-expression of Bax, caspase 9 and caspase 3, leading to DNA damage and activation of P53.