We found elevated levels of CD27+IgM+ B cells, activated memory B-cell populations (CD20+CD27+CD24+CXCR4+cMYC+ B cells and CD20+CD24+CXCR4+CXCR5+ B cells), and CD20+CXCR4hiAICDA+ B cells with malignant and pre-lymphoma phenotypes in the circulation of HIV+ cART-naïve samples at 6 to 36 months before their NHL diagnosis. Here, CXCR4 is linked to non-Hodgkin lymphoma.