Summary In vitro (FLC-Vt) or in vivo (FLC-V) passaged Friend erythroleukaemia cells of DBA/2 origin were tested for susceptibility to natural resistance (NR) in vivo or to NK cell activity in vitro. Scarcely oncogenic FLC-Vt cells were highly susceptible to in vivo NR (measured as rapid organ clearance or growth inhibition in lethally irradiated mice) or to in vitro NK attack. Conversely, highly oncogenic FLC-V cells were weakly susceptible to NR and to NK as well. These data seem to point out that natural immunity, which is up-regulated by endogenous or exogenous interferons, can play a significant role in surveillance against mouse leukaemic cells of retrovirus origin.It has been reported that the in vivo tumour suppressive effects of interferon (IFN) against in vitro and in vivo passaged Friend erythroleukaemia cells (FLC-Vt and FLC-V, respectively), derived from DBA/2 mice infected with Friend virus, might involve activation of immune host's mechanism rather than acting directly on tumour cells (Belardelli et al., 1982a;Gresser et al., 1983Gresser et al., , 1988). This hypothesis was based on the isolation of FLC clones differing for sensitivity to IFN-alpha-beta-induced antiproliferative effects under in vitro conditions (Affabris et al., 1982). Using the highly tumorigenic IFN-sensitive (745) or IFN-resistant (3C18) FLC-V clones it was demonstrated that exogenous IFN preparations could suppress FLC-V in vivo growth, irrespective of the differences in IFN sensitivity (Belardelli et al., 1982a;Gresser et al., 1988). Moreover, it was observed that the low oncogenicity of both 745-and 3C18-FLC-Vt clones was due to host's reactivity enhanced by endogenous IFN, since pretreatment of mice with anti-IFN antibodies augmented FLC-Vt tumorigenicity (Gresser et al., 1983).Previous investigations were carried out to detect the possible origin of host's immune reactivity involved in the indirect antitumour effects of IFN. The results showed that in vivo natural resistance (NR) against both FLC-Vt (Iorio et al., 1986) and FLC-V clones could play a significant role in this system. The present study shows that the low oncogenic FLC-Vt clone is subjected to strong NR in syngeneic DBA/2 mice and is more susceptible to NR effectors as compared with the highly oncogenic FLC-V. Irradiation Animals were subjected to total body irradiation using a cobalt-60 irradiator (Hot Spot MKIV, Harwell, England), delivering gamma-rays at the rate of 800Rmin-m.Organ clearance of 125I-iodedeoxyuridine (12 5IUdR)-labelled cells The general procedure for this assay has been previously described (Riccardi et al., 1980). Briefly 25 x 106 FLC-V or FLC-Vt in 50ml of RPMI 1640 medium supplemented with 10% fetal calf serum were incubated overnight at 37°C in a