HL-60 is induced to differentiate by retinoic acid (RA) to mature granulocyte-like cells. We found that pretreatment of HL-60 with pertussis toxin (PT) inhibited differentiation induced by various concentrations of RA. This inhibition was observed when PT was prior to the addition of RA. PT ADP-ribosylated a 39,000 Da protein of membrane fraction of HL-60 and did not increase an intracellular cyclic adenosine-3':5'-monophosphate level, indicating that Go, a guanine nucleotide-binding protein, involves signal transduction for RA-induced differentiation. However, Go does not appear to be obligatory for the common pathway of induction of HL-60 differentiation, because PT showed a little or no effect on differentiation induced by other inducers such as 1 alpha,25-dihydroxyvitamin D3, tumor necrosis factor, interferon-gamma, lymphotoxin, prostaglandin E2, cholera toxin, and dimethylsulfoxide.