C57BL/6 (B6). FcγRIIb−/−. Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type–specific role of FcγRIIb in Yaa-associated lupus, we established B cell–(CD19 Cre. Yaa), myeloid cell–(C/EBPα Cre. Yaa), and dendritic cell–(DC)(CD11c Cre. Yaa) specific FcγRIIb-deficient B6. Yaa mouse strains. CD19 Cre. Yaa mice developed milder lupus than B6. FcγRIIb−/−. Yaa mice, indicating that FcγRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα Cre. Yaa mice also showed autoantibody production and mild lupus similar to that in CD19 Cre. Yaa mice, whereas CD11c Cre. Yaa mice stayed disease free. These observations indicate that FcγRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6. FcγRIIb−/−. Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-1− but not Gr-1+ monocyte was increased in B6. FcγRIIb−/−. Yaa and C/EBPα Cre. Yaa but not CD19 Cre. Yaa mice, suggesting a link between FcγRIIb deficiency on myeloid cells and the high frequency of Gr-1− monocytes. RNA sequencing revealed that compared with Gr-1+ monocytes, Gr-1− monocytes expressed higher levels of the B cell–stimulating cytokines BSF-3, IL-10, and IL-1β, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa-associated lupus nephritis, FcγRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-1− monocytes are the most likely candidate myeloid cells involved.