Our results demonstrate that prediction of C-terminal antigen processing achieves high accuracy on MHC-I (AUC of 0.91), while it remains challenging for MHC-II (AUC of 0.66). Moreover, we evaluated the performance of NetCleave and one of the most widely used current standards, NetChop3.1, for the evaluation of four independent immunogenicity datasets (H2-Db, H2-Kb, HLA-A*02:01 and HLAB: 07:02). Overall, we demonstrate that NetCleave outperforms NetChop3.1 for the prediction of Cterminal processing, and we provide one of the first evidences that C-terminal processing predictions may help in the discovery of immunogenic peptides.