Based on phylogenetic analysis and chromosomal mapping, the orphan receptor RDC1 was proposed to be a chemokine receptor. In this study we examined the expression of RDC1 on leukocytes by measuring mRNA levels and receptor expression using a new specific mAb. Both mRNA and protein levels were high in monocytes and B cells, relatively low on immature dendritic cells (DC), and up-regulated during final stages of maturation. Strikingly, in mature plasmacytoid DC the mRNA was up-regulated, but did not correlate with protein surface expression. We indeed report that CpG-activated plasmacytoid DC produce a putative ligand for RDC1, which selectively down-regulates RDC1, but not CXCR4 on primary human B cells. RDC1 expression was found to be tightly regulated during B cell development and differentiation. In blood-derived switch memory B cells, the expression of RDC1 appeared to correlate with the ability to differentiate into plasma cells upon activation, suggesting that RDC1 is a marker for memory B cells, which are competent to become Ab-secreting cells.