Ciprofibrate, an hypolipidaemic peroxisome proliferator, induced differentiation of HL-60 cells. The effect was greatly potentiated by phorbol 12-myristate 13-acetate at a concentration where neither phorbol ester nor ciprofibrate alone had any effect on these cells. As occurs for HL-60 cell differentiation induced by high phorbol ester concentration, the ciprofibrate-induced phorbol ester-dependent differentiation of HL-60 cells proceeded through the monocytic/macrophage pathway and induced the phosphorylation of proteins with similar molecular weights suggesting that increased protein kinase C activity may be involved in the effect. The peroxisome proliferator-activated receptor (PPARα) transcription factor is expressed in HL-60 cells, but no changes were observed in its expression upon HL-60 cell differentiation.