Differentiation-promoting effects of interferon-gamma IFN-y), both alone and in combination with retinoic acid RA), were studied on the human neuroblastoma cell line, LA-N-5. The results show that IFN-y inhibited the growth and induced morphological differentiation in a dose-and timedependent manner with measurable effects appearing at 2& 40 IUlml after 3 to 4 days of treatment in vitro. Acetylcholinestense activity, used as a biochemical index of neuroblastoma differentiation, increased up to 2.5-fold in the presence of 1FN-y with a half maximal concentration of approximately 100 IU/ml. Concomitantly, modest IFN-induced increases (S2-fold) in choline acetyltransferase (ChAT) and tymine hydroxylw (TH) activities were seen. Combination treatment of cells with IFN-y and RA resulted in synergistic effects on morphological differentiation, growth inhibition and induction of ChAT. Reversal of IFN-y's ability to influence neuroblastoma cell growth as well as potentiate the anti-tumor effects of RA was obtained in the presence of an antibody against the 1FN-y receptor, implying receptor-mediated physiological events. Taken together, these data confirm the differentiating effects of IFN-y on human neuroblastoma cells t that combination therapy with RA may be ben-%i:#% treatment of this disease.