Background: The role of natural killer (NK) cells in plasma cell diseases has not yet been fully characterized. Case Report: We present the case of a 47-year-old man with an extremely aggressive extramedullary plasmacytoma of the lung with associated cutaneous lesions, whose disease was accompanied by a significantly decreased number of NK cells (CD56+, CD16+, CD3–) in the peripheral blood, very low NK cell activity levels, and a decreased interleukin-2 production from cultured cells in vitro. Histology and immunohistochemistry of the lung and cutaneous lesions identified that the tumor was composed of clonal plasma cells which were CD38+++, CD138+++, lambda chain+, kappa chain–, and cytokeratin–. Bone marrow histology and cytology were initially normal. The disease progressed rapidly despite local radiotherapy and systemic chemotherapy, and the patient died shortly after diagnosis. Conclusions: Cutaneous involvement in extramedullary plasmacytoma represents a clinically aggressive variant of plasma cell tumor, which runs a rapid course and has associated devastating effects on the patient’s innate immune system.