The effect of recombinant hybrid interferon (IFN)-alpha A/D either alone or in combination with retinoic acid (RA) on induction of differentiation of the human promyelocytic leukemia cell line HL-60 was studied. The combination of 10 nM RA and IFN-alpha A/D at concentrations of 120 units/ml and higher induces differentiation into cells having many monocytic characteristics such as monocyte-like morphology, ability of superoxide anion production, antibody-dependent cellular cytotoxicity, and nonspecific esterase activity. However, this combination does not induce an increase in IgG Fc receptors (Fc gamma R) and immunoerythrophagocytosis. IFN-alpha A/D alone shows essentially no effect on these parameters. Pretreatment of HL-60 with IFN-alpha A/D blocks the Fc gamma R-increasing activity of IFN-alpha A, IFN-alpha D, and IFN-gamma. This block is complete after a 2-h pretreatment for IFN-alpha A and IFN-alpha D and after a 6-h pretreatment for IFN-gamma. Furthermore, an increase in Fc gamma R-mediated phagocytosis is also suppressed by the pretreatment. However, IFN-alpha A/D does not suppress superoxide anion production. These results indicate that the block of an Fc gamma R-increase by IFN-alpha A/D has not resulted in the competitive inhibition at IFN receptors, but may occur in intracellular events such as postreceptor transduction for the expression of Fc gamma R.