Summary. We analysed CD56 expression in 70 patients with multiple myeloma (MM) to determine its clinicopathological and prognostic significance. Fifty-five (79%) patients were CD56+. CD56– patients (n = 15) had higher β2 microglobulin levels and a higher incidence of extramedullary disease, Bence Jones protein, renal insufficiency and thrombocytopenia than CD56+ patients. Their myelomas more frequently had a plasmablastic morphology. Overall survival was significantly lower in CD56– than CD56+ patients (22 vs 63 months, P = 0·0002). We conclude that CD56– MM is a discrete entity associated with more aggressive disease. The higher incidence of plasmablastic cases suggested that CD56– MM may develop from a less mature plasma cell than CD56+ MM.