With a simple infusion experiment it was estimated that at least six (LEA, AEA, DHEA, PEA, OEA and SEA) out of 8 (also including 2-AG and NADA) targeted endocannabinoids could be corrected with the same PCIS. Six characteristics of a promising PCIS candidate were defined and used to select 2F-anandamide (2F-AEA) to test as a PCIS for the endocannabinoids in this study. This choice was successful, as became clear after optimizing its concentration and applying three approaches to assess its performance, all leading to similar conclusions: the PCIS 2F-AEA was not successful in the matrix effect correction of NADA, but for the other analytes it could improve the matrix effect values for various matrices, the precision over matrices and over matrix concentrations, and the dilutional linearity and precision to within acceptable limits.