(1) Firstly, we assessed the transcriptome highlighting different signatures of the B cell subpopulations in COVID-19-infected subjects showing a downregulation of FXYD, HLA-DRB1, and RPS20 in memory B cells; a downregulation of MT-ATP8 and HLA-DQA1 in naïve cells; a downregulation of RPS4Y1 in activated B cells; and a downregulation of IGHV3-73 in the plasma cells. Here, RPS4Y1 is linked to COVID-19.