The antibody-dependent cellular cytotoxicity (ADCC) effector function of natural killer (NK) cells is one of the known mechanisms of action for rituximab-based anti-cancer immunotherapy. Inhibition of the ADCC function of NK cells through interactions between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands is associated with resistance of cancers to rituximab. In this study, we deeply investigated the impact of KIR, HLA class I, and CD16 genotypes on rituximab-dependent NK cell responses in both an in vitro cellular model from healthy blood donors and ex vivo rituximab-treated non-Hodgkin lymphoma (NHL) patients. We highlight that an HLA environment with limited KIR ligands is beneficial to promoting a higher frequency of KIR+ NK cells including both educated and uneducated NK cells, two NK cell compartments that demonstrate higher rituximab-dependent degranulation than KIR- NK cells. In contrast, a substantial KIR ligand environment favors a higher frequency of poorly effective KIR- NK cells and numerous functional KIR/HLA inhibitions of educated KIR+ NK cells. These phenomena explain why NHL patients with limited KIR ligands respond better to rituximab. In this HLA environment, CD16 polymorphism appears to have a collateral effect. Furthermore, we show the synergic effect of KIR2DS1, which strongly potentiates NK cell ADCC from C2- blood donors against C2+ target cells. Taken together, these results pave the way for stronger prediction of rituximab responses for NHL patients. HLA class I typing and peripheral blood KIR+ NK cell frequency could be simple and useful markers for predicting rituximab response.Keywords: KIR; adcc; cd16; hla; nk cells; non hodgkin lymphoma; rituximab.