This study was prompted by recent reports that epoxyeicosatrienoic (EET) and epoxyeicosatetraenoic (EEQ) acids accelerate tumor growth and metastasis by stimulation of angiogenesis, while eicosapentaenoic (EPA) and epoxydocosapentaenoic (EDP) acids inhibit angiogenesis, tumor growth, and metastasis. Cytochrome P450 epoxygenases convert arachidonic to EET, eicosapentaenoic acid to EEQ, and docosahexaenoic acid to EDP, which are found both in free form and esterified to glycerophosphocholine (GPC). Both free and esterified epoxy (EP) acids are also formed during lipid autoxidation. For biological activity, the GPC-EP requires hydrolysis, which we presumed could occur by sPLA2s located in proximity of lipoproteins carrying the lipid epoxides. The plasma lipoproteins were isolated by ultracentrifugation and analyzed by LC/ESI-MS. The GPC-EPs were identified by reference to standards and to retention times of phospholipid masses. The GPC-EP monoepoxides (corrected for isobaric ether overlaps) in stored human LDL, HDL, HDL3, or APHDL ranged from 0 to 1 nmol/mg protein, but during 4-h incubation at 37°C increased to 1–5 nmol/mg protein. An incubation of autoxidized LDL, HDL, or HDL3 with 1 μg/ml of group V or X sPLA2 resulted in complete hydrolysis of diacyl GPC epoxide esters. Group IIA sPLA2 at 1 μg/ml failed to produce significant hydrolysis in 4 h, but at 2.5 μg/ml in 8 h yielded almost 80% hydrolysis, which represented complete diacyl GPC-EP hydrolysis. The present study shows that group IIA, V, and X sPLA2s are capable of extensive hydrolysis of PtdCho epoxides of autoxidized plasma lipoproteins. Therefore, all three human sPLA2s were potentially capable of inducing epoxide biological activity in vivo.