Contrary to single deficiency due to loss of the C-terminal region of RAG2 (core RAG2) or XLF that do not harbour major defects in V(D)J recombination, we find that combined core RAG2 and XLF deficiency leads to a block in lymphocyte development at the progenitor stage when V(D)J recombination occurs, very reminiscent of the severe combined immunodeficiency phenotype observed in cNHEJ-deficient mice. This evidence concerns the gene RAG2 and Immunodeficiency.