Leptin, the adipocyte-secreted hormone, is known to function as an immunomodulatory regulator. Thus, we have recently found that human leptin promotes stimulation and proliferation of human peripheral blood mononuclear cells. Besides, we have also demonstrated that leptin triggers PI3K and p42/44 MAPK signaling pathways. In the present work, we sought to study the possible effect of leptin on cell survival and apoptosis, as well as the mechanisms underlying these effects. We have cultured human PBMC in serum-free conditions to assess the effect of leptin on cell survival and apoptosis. We have assayed the early phases of apoptosis by flow cytometric detection of phosphatidylserine expression using fluorescein isothiocyanate (FITC)-labelled Annexin V, simultaneously with dye exclusion of propidium iodide (PI), to discriminate intact cells, apoptotic, and necrotic cells. We have found that leptin promotes dose-dependent cell survival of monocytes after 24-96 h of serum-free culture. This effect of leptin on monocyte survival was completely reversed by blocking p42/44 MAPK activation employing the MEK inhibitor PD98059, whereas it was not affected by PI3K inhibition using Wortmannin. Leptin promotes this survival effect by preventing the apoptosis of monocyte cells, via MAPK activation. Thus, p42/44 MAPK inhibition, using PD98059, but not PI3K inhibition, employing Wortmannin, blocked the protective effect of leptin preventing apoptosis of monocytes cultured in the absence of serum. These data suggest that leptin is a trophic factor for the survival of blood monocytes and this effect is mediated by the p42/44 MAPK pathway.