Somatic cell hybrids between mouse peritioneal macrophages and HT-1080 human fibrosarcoma cells lose mouse chromosomes and retain the entire complement of human chromosomes. In contrast, somatic cell hybrids between cells derived from two different mouse continuous cell lines and HT-1080 human cells were found to lose human chromosomes preferentially. Loss of mouse chromosomes is not a general property of hybrids between mouse macrophages and transformed human cells; the hybridization of mouse macrophages with cells derived from five different human fibroblast lines transformed by simian virus 40 resulted in the production of hybrid clones that preferentially lost human chromosomes.