Mesenchymal stem cells (MSCs) are widely distributed throughout the body. Despite intensive studies on the immunosuppressive effect of MSCs, little is known about whether MSCs affect lymphocyte apoptosis. We investigated the effect of MSCs on the spontaneous death of lymphocytes and found that MSCs inhibit the apoptosis of splenocytes and thymocytes as well as purified T and B cells. The protective effect of MSCs was absent when lymphocytes were not in contact with MSCs, indicating that the anti-apoptotic effect is exerted through direct interaction between MSCs and lymphocytes. Interestingly, this anti-apoptotic effect could be inhibited by neutralization of IL-6. Consequently, we found that the expression of IL-6 by MSCs was augmented by contact with lymphocytes. Taken together, these results demonstrate that IL-6 plays an important role in the inhibition of lymphocyte apoptosis by MSCs.