Fatty Acid Amide Hydrolase (FAAH) is one of the enzymes responsible of endocannabinoids metabolism. The inhibition of FAAH is a useful and indirect strategy to raise endogenous cannabinoid concentrations, which would be useful for the treatment of various pathological processes in which cannabinoid concentrations are lowered. In the present work, we present an extensive 3D-QSAR/CoMSIA study on a series of 90 irreversible inhibitors of FAAH of pyrimidinyl-piperazine-carboxamide structure. The final model obtained was extensively validated (q2 = 0.734; r2test = 0.966; r2m = 0.723), and based on the information derived from the contour maps we reported a series of 10 new compounds designed as powerful FAAH inhibitors (pIC50 of the best-proposed compounds = 12.196; 12.416).