Human peripheral-blood monocytes, when cultured in the absence of serum, are prevented to differentiate to macrophages (M-phi). Instead, they develop into accessory cells which by various properties resemble dendritic cells. Signals that control development either into M-phi or monocyte-derived accessory cells (m-AC) have been investigated by us. By applying such triggers, m-AC phenotypes and functions approached those known from lymphoid dendritic cells. Only the monocyte marker CD14, which is absent from dendritic cells, remained positive on m-AC as a last indicator of the monocytic origin of the cells. We now report that this most stable marker of the monocyte/M-phi lineage can completely be down-regulated by combining tissue culture techniques with the inductive property of interleukin-4. Evidence has also been obtained by us that the conversion of monocytes into both m-AC and M-phi represents a true differentiation, as demonstrated by the expression of the nuclear marker lamin A/C.