A striking feature of myeloma plasma cells concerns their expression of the neural cell adhesion molecule (N-CAM). The regulation of this particular expression is, however, not known. In this study, the N-CAM (CD56) gene regulation was examined in a panel of multiple myeloma (MM) cell lines. In this panel, both N-CAM-positive and -negative cells were analysed, reflecting the in vivo situation where a minority of MM patients have CD56-negative plasma cells at diagnosis or where in cases of extramedullary involvement CD56 expression decreases. At least two N-CAM mRNAs were found in the cell lines expressing the 140 kDa isoform. With one exception, no N-CAM transcripts could be detected in the N-CAM-negative cell lines. No structural differences could be found in the genomic organization of the N-CAM gene, or in the regulatory promoter region when CD56-positive and -negative cell lines were compared. In transfection studies, however, transcriptional activity of the N-CAM promoter was observed in N-CAM-negative cells, leading us to conclude that the up-regulation of N-CAM in MM cannot be explained by a simple transcriptional gene activation.