Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work, the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using 20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%–100%). Furthermore, we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme human longevity. In addition, we also show that extreme longevity presents a fatty acid profile resistant to lipid peroxidation. Our findings indicate that lipidomic signature is an optimized feature associated with extreme human longevity. Further, specific lipid molecular species and lipid unsaturation arose as potential biomarkers of longevity.