Human mononuclear cells derived from peripheral blood of adult donors (PBMC) or from neonatal cord blood (CBMC) were found to be equally sensitive to the protective effect of alpha- and beta-interferons (IFNs) against the infection with HTLV-I during long-term culture. The effect of IFNs was evidenced by a remarkable reduction of the number of virus-positive cells during culture as evaluated by indirect immunofluorescence for the p19 virus core protein. Moreover, the appearance of p19-positive immortalized clones was inhibited by IFNs in PBMC co-cultures, whereas it was delayed in CBMC cultures. These kinetics are in relation with the higher permissivity of CBMC to the virus in comparison with PBMC, since in CBMC cultures infected cells can be clearly detected starting already 1 week post-infection (p.i.), whereas in PBMC cultures their appearance time is approximately at the 6th week p.i. IFNs acted by 'priming' PBMC and CBMC to an active antiviral competence, since one single treatment with 1000 IU/ml of alpha- or beta-IFN at the onset of the co-culture of mononuclear cells with irradiated virus-donor cells was able to maintain very low levels of infection for approximately 6 weeks in CBMC cultures and at least for 18 weeks in PBMC cultures. As a consequence, it seems likely that IFN action is mediated by the expression of a defined, although not completely identified, set of genes in the host cells.