In this study, we show that malignant plasma cells from patients with either primary (n=12) or secondary (n=15) plasma cell leukemia (PCL) do not express CD56 at all, neither in the bone marrow nor the peripheral blood in 81% of cases. On the other hand, multiple myeloma (MM) at diagnosis overexpress it in 63 of 94 (67%) cases (P=0.0001). In three secondary PCL evaluated serially, CD56 was also lacking at diagnosis showing that CD56 is not downregulated at the end stage of the disease but rather not upregulated in this subset of patients. This last concept is strengthened by the observation that 29% of MM patients lacking CD56 or weakly expressing it at diagnosis present a detectable leukemic phase vs 11% only in CD561 MM (P=0.06). Forty percent of all the CD56(-/weak) malignant plasma cell disorders present or develop a leukemic phase vs only 15% of CD56+ cases (P < 0.008). CD56(-/weak) MM subset is also associated with a significantly less aggressive osteolytic potential (P=0.012). We conclude that the lack or weak expression of CD56 is a characteristic feature of PCL but also delineates a special subset of MM at diagnosis mainly characterized by a lower osteolytic potential and a trend for malignant plasma cells to circulate in the peripheral blood more overtly.