CD27 expression was evaluated on normal plasma cells (PC), PC from patients with multiple myeloma (MM) at diagnosis or relapse and on human myeloma cell lines (HMCL). CD27 was expressed by normal PC but was lacking in PC from MM patients at diagnosis (36%) and relapse (47%), and in HMCL (92%). The prognostic impact of CD27 expression was evaluated in 42 patients with de novo MM. Overall survival was 92% at 3 years in CD27(+) vs. 50% in CD27(-) MM (P = 0.017). CD27 expression seems to delineate two important subsets of MM with different presenting features and clinical outcomes.