Endemic Burkitt lymphoma (BL) is one of the most common pediatric cancers in sub-Saharan Africa. This cancer is associated with Epstein-Barr virus (EBV) and malaria co-infections during early childhood. Because Natural Killer (NK) cells are essential in anti-viral and anti-tumor surveillance, it is crucial to determine their role in fighting EBV-associated cancers. In our previous studies, we described an accumulation of an atypical CD56^negCD16^pos NK cell subset in BL. Despite their expression of cytotoxic molecules, these cells had poor direct cytotoxicity. Therefore, we assessed CD56^negCD16^pos NK cells for their in vitro antibody dependent cellular cytotoxicity (ADCC) potential with rituximab (therapeutic antibody against CD20) using peripheral blood mononuclear cells (PBMCs) from children with and without cancer. We used 6 BL cell lines as target cells: Akata, Mutu, BL717, BL740 (EBV-type1) and BL719, BL725 (EBV-type2). We found that CD56^negCD16^pos NK cells were indeed capable of ADCC indicated by a significant increase of CD107a expression (3 to 18%) in presence of rituximab (ranging from p=0.02 to p=0.0005, depending on target-cell). However, they were not as efficient as CD56^dimCD16^pos cells which showed significantly stronger degranulation compared to CD56^neg NK cells (mean of CD107a^pos cells of 28% versus 18% respectively, from p=0.001 to p<0.0001, depending on target-cell). We also observed heterogeneity in the lysis of BL targets in response to ADCC, with EBV-type1 cell lines being preferentially killed in presence of rituximab (mean of % lysis of ~60% at 9:1 E:T ratio); whereas EBV-type2 cell lines were killed without rituximab (mean of ~60%, same E:T ratio), suggesting an antibody-independent mechanism at play. Thus, ADCC efficiency was diminished for CD56^negCD16^pos NK cells that are associated with EBV positive BL, and strongly varied by BL target cell origin and type, highlighting the potential to personalize rituximab-based immunotherapy of BL.