Expression of CD27 on malignant plasma cells (PC) (CD138+CD38++) was analysed in a cross-sectional study of bone marrow (BM) samples from multiple myeloma (MM) patients (n = 28), monoclonal gammopathy of undetermined significance (MGUS) patients (n = 6) and BM PC from healthy donors (n = 4). MM PC expressed CD27 with a variable, lower intensity pattern compared with the consistent high expression in MGUS and healthy donors. MM patients in complete clinical remission displayed a higher percentage of CD27+ PC compared with patients at diagnosis, relapse or in partial remission. In MM, loss of CD27 correlated with loss of CD19 (R2 = 0.4, P < 0.0001). Human MM cell lines (n = 9) did not express CD27 whereas de novo plasma cell leukaemia (PCL) (n = 3) had a high expression. Re-analysis of a cDNA microarray data set, generated from newly diagnosed MM patients (n = 74), demonstrated that the MM subgroup with the highest prevalence of poor prognostic factors had the lowest CD27 mRNA expression. Fluorescence-activated cell sorting and allele-specific oligonucleotide polymerase chain reaction showed that both CD27+ and CD27- PC subpopulations in MM can belong to the clonal disorder. In conclusion, CD27 is heterogeneously expressed on MM PC and loss of CD27 expression might have prognostic value in MM.