The aim of this prospective, long-term study was to define the flow cytometric characteristics of plasma cell CD56 expression as well as determine the clinical characteristics of 204 multiple myeloma (MM) patients and 26 plasma cell leukemia (PCL) patients with regard to CD56 expression. CD56 expression intensity was determined by measurement of antigen molecules on the cell defined as Antibodies Bound per Cell (ABC) and calculation of Relative Fluorescence Intensity (RFI). CD56 expression was found in 66% of MM and 54% of PCL cases. The RFI values for individual MM patients ranged from 7.6 to 27.4 while ABC values on MM plasma cells from 2255 to 58469. There was a correlation between the proportion of all bone marrow CD38(++)/CD138(+) cells with CD56 expression and ABC and RFI indices. With regard to CD56 expression positive patients, the CD56(-) MM patients presented lower frequency of osteolysis (p = 0.01). The median survival was 48 months in CD56(+) patients and 43 months (p = 0.84) in CD56(-) cases. In conclusion, CD56 expression carries no distinct adverse prognosis and the lack of CD56 expression does not define a unique clinicopathological or prognostic entity in MM. A remarkable heterogeneity of CD56 expression intensity in CD56(+) patients imposes the necessity of determining CD56 expression intensity in candidates to antibody-based therapy.