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.