Endoglin plays a crucial role in physiopathological processes such as Hereditary Hemorrhagic Telangiectasia (HHT), preeclampsia or cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of endoglin have been reported, L-endoglin and S-endoglin. While L-endoglin is the predominant variant, an increased expression of the S-endoglin isoform during senescence of the myeloid lineage, in human and murine models, was observed. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-endoglin and S-endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-endoglin expression led to decreased cellular proliferation and survival response to GM-CSF-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggest a non-redundant role for each endoglin isoform in monocyte biology. In addition, we find that S-endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.