The survival of leukaemic blasts contributes to the pathological mechanism of acute promyelocytic leukaemia (APL). While treatment of APL using retinoic acid (RA) is a model of differentiation therapy, little is known about possible effects of this treatment on the Fas/FasL system. Investigation of APL cells from patients undergoing differentiation therapy with RA and of promyelocytic HL-60 and monoblastic U-937 cells cultured with RA revealed a reduction of surface expression of both Fas and its ligand. Accordingly, the sensitivity of the cells to anti-Fas-induced apoptosis decreased proportionally and the reduced expression of FasL resulted in a decreased ability of the leukaemic cells to induce apoptosis in T cells. Our findings demonstrate that there are significant changes in Fas and FasL expression during RA treatment of APL, which probably have consequences for the interaction between host immune and leukaemia cells, and thus may be involved in the beneficial effects of differentiation therapy.