Human T cells co-infected with the human immunodeficiency virus type 1 (HIV-1) and the xenotropic or dual-tropic mouse type C virus (MuLV) give rise, by phenotypic mixing, to progeny virus that can transfer HIV-1 into a wide variety of mammalian and avian cells. Differences in the extent of HIV-1 replication in these animal cells can be observed. Replication is best in human cells, but occurs substantially in cells from many animal species including mink, horse, and bush wallaby. Virus production in murine and avian cells is very limited. These results confirm that the major block to HIV-1 infection of animal cells is at the cellular surface but that intracellular regulation of viral replication is also involved. Moreover, an enhancement of HIV-1 cytopathic effects can be seen in human cells co-infected by MuLV. All these data suggest phenotypically mixed viruses might be useful for developing an animal model system for studying AIDS, and that the pathological expression of HIV-1 could be modified by the presence in cells of other retroviruses. They also indicate a potential mechanism by which HIV strains can be generated with an increased ability to spread in nature.