ABSTRACT In this study, we identified whether mitogen‐activated protein kinases (MAPKs) mediate the effects of angiopoietin‐1 (Ang‐1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang‐1 (300 ng/ml) evoked within 15–30 min a 15‐fold and a 5‐fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI‐3 kinase pathway attenuated Ang‐1‐induced ERK1/2 phosphorylation at a level up‐stream from Raf and MEK1/2, but these inhibitors augmented Ang‐1‐induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang‐1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase‐9, ‐7, and ‐3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang‐1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang‐1. We conclude that both anti‐ (ERK1/2) and pro‐ (p38) apoptotic members of MAPKs are simultaneously activated by Ang‐1 in endothelial cells and that activation of ERK1/2 by Ang‐1 is mediated through the PI‐3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI‐3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang‐1.