Abstract Multiple myeloma (MM) and plasmacytomas are cancers of antibody-secreting cells (ASCs). PRDM1/BLIMP1 is an essential regulator of ASC development. Histologic evidence shows that 100% of MM expresses PRDM1/BLIMP1, indicating that PRDM1/BLIMP1 is important for the development or persistence of MM. In contrast, some diffuse large B-cell lymphomas (DLBCLs) lose PRDM1 expression, suggesting that PRDM1 may act as a tumor suppressor in DLBCL. Thus, the role of PRDM1/BLIMP1 in transformation of mature B cells is unclear. We have used a plasmacytoma-prone transgenic mouse model to study the effect of Blimp1 loss on plasmacytoma prevalence, latency, and phenotype. Two possible outcomes could be envisaged: loss of Blimp1 might decrease plasmacytoma prevalence, through reduction of plasma cells, and so the number of susceptible transformation targets. Alternatively, Blimp1 may participate in the transformation process itself. Our results support the latter scenario, showing that decreasing Blimp1 dosage does not change plasma cell number in nontransgenic mice in vivo, but it significantly reduces plasmacytoma prevalence in transgenic mice. Loss of functional Blimp1 completely prevents plasmacytoma formation in this tumor model. These observations suggest that Blimp1 is limiting for plasma cell transformation and thus has potential as a target for new therapies to combat MM.