A middle-aged woman with a 13-year history of systemic lupus erythematosus, lupus nephritis, antiphospholipid syndrome, and recurrent deep vein thrombosis presented with diffuse bulky lymphadenopathy (largest, 5.1 cm). Imaging studies showed mild splenomegaly. Laboratory studies were significant for a microcytic anemia (hemoglobin, 10.3 g/dL; mean corpuscular volume, 76.4 fL) and hypergammaglobulinemia (immunoglobulin G [IgG], 6590 mg/dL). Serum protein electrophoresis (panel A, serum protein electrophoresis gel control [left] and patient sample [right]) showed 2 bands of restricted electrophoretic mobility (asterisks). Concurrent serum immunofixation (panel B) showed 2 γ heavy chain bands (arrowheads) without corresponding light chain bands. A lymph node biopsy showed architectural effacement by a proliferation of small-to-medium-sized atypical lymphoid cells (panel C, hematoxylin and eosin [H&E], original magnification ×10) with plasmacytic differentiation (panels D and E, H&E, original magnification ×20 and ×40, respectively). The cells were positive for CD138 (panel F, CD138, original magnification ×20) but lacked κ and λ light chains (panel G, κ, original magnification ×10; panel H, λ, original magnification ×10). Cells were also positive for IgG (panel I, IgG, original magnification ×10). These findings are consistent with γ heavy chain disease (GHCD). A bone marrow biopsy and MYD88 mutational analysis were not performed. The patient was treated with bortezomib, cyclophosphamide, and steroids. Four months later, she died of diffuse alveolar damage in the setting of volume overload.This case highlights the association between autoimmune disorders and GHCD and underscores the importance of recognizing and diagnosing this rare lymphoproliferative disorder.