A 43-year-old woman who was receiving oral antibiotics for several days for a superficial foot infection developed a persistent rash, fever, and lymphadenopathy, despite discontinuation of the antibiotic and administration of steroids for a presumed drug reaction. Hours after a subsequent visit to the emergency room for worsening symptoms, she died at home. At autopsy, there was a florid, systemic proliferation of polyclonal plasma cells and immunoblasts infiltrating nearly every organ and tissue of the body, most notably the lymph nodes and spleen. The polyclonal nature of the process was confirmed by immunofixation electrophoresis and immunohistochemistry. Cases of fatal polyclonal systemic immunoblast proliferations are extremely rare, and the trigger for such proliferations is not always known. We review the literature on this unusual entity and discuss the clinical and pathologic findings.