High nonesterified fatty acid (NEFA) concentrations, as observed in the metabolic syndrome, trigger apoptosis of human umbilical vein endothelial cells. Since endothelial apoptosis may contribute to atherothrombosis, we studied the apoptotic susceptibility of human coronary artery endothelial cells (HCAECs) toward selected NEFAs and the underlying mechanisms. HCAECs were treated with single or combined NEFAs. Apoptosis was quantified by flow cytometry, nuclear factor kappaB (NFkappaB) activation by electrophoretic mobility shift assay, and secreted cytokines by enzyme-linked immunosorbent assay. Treatment of HCAECs with saturated NEFAs (palmitate and stearate) increased apoptosis up to fivefold (P < 0.05; n = 4). Unsaturated NEFAs (palmitoleate, oleate, and linoleate) did not promote apoptosis but prevented stearate-induced apoptosis (P < 0.05; n = 4). Saturated NEFA-induced apoptosis neither depended on ceramide formation nor on oxidative NEFA catabolism. However, NEFA activation via acyl-CoA formation was essential. Stearate activated NFkappaB and linoleate impaired stearate-induced NFkappaB activation. Pharmacological inhibition of NFkappaB and inhibitor of kappaB kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFkappaB was not attributable to NEFA-induced cytokine production. In conclusion, NEFAs display differential effects on HCAEC survival; saturated NEFAs (palmitate and stearate) are proapoptotic, and unsaturated NEFAs (palmitoleate, oleate, and linoleate) are antilipoapoptotic. Mechanistically, promotion of HCAEC apoptosis by saturated NEFA requires acyl-CoA formation, IKK, and NFkappaB activation.