The effect of retinoic acid (RA) on the antiviral activity of interferons (IFNs) alpha and beta in the U937 and WISH cells was examined to ascertain whether or not RA could reduce the effectiveness of IFN-induced resistance to viral infection. Our results indicate that in the U937 cells, RA (0.1-1.0 microM) had neither enhancing nor suppressive effect on the antiviral activity of IFN-alpha or beta against the Semliki Forest virus (SFV). However, in the WISH cells, RA had different effects on IFNs alpha and beta. Thus, while RA (0.1-50 microM) invariably suppressed the activity of IFN-alpha, it enhanced the action of IFN-beta at low dose (0.1-1.0 microM) but became suppressive at higher concentrations (greater than or equal to 10 microM). Furthermore, higher antiviral activity was consistently obtained when RA (0.1-10 microM) was added prior to either IFN-alpha or IFN-beta comparing to cultures with IFN alone. In addition, direct correlation between antiviral activity and the amplitude of 2-5 oligoadenylate (A) synthetase activity was not observed. These results suggest that modulation of IFN antiviral activity by RA varies with different systems and is dependent on the sequence of treatment.