DBA/2 mice were injected i.v. with IFN alpha/beta-resistant 3CI8 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN alpha/beta treatment of FLC-injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN alpha/beta in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The anti-tumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC-injected DBA/2 mice were treated with antibodies to asialo-GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN alpha/beta treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN-induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN alpha/beta in this experimental model.