APOBEC3 family proteins are human DNA cytosine deaminases recognized for contributing to the restriction of human immunodeficiency virus type 1 (HIV-1). Prior studies have demonstrated that APOBEC3D, APOBEC3F and APOBEC3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in vivo. In addition to these three APOBEC3 proteins, human APOBEC3H is polymorphic and can be categorized into two phenotypes: stable and unstable. However, the anti-viral effect of endogenous APOBEC3H in vivo and the effect of APOBEC3H heterogeneity on HIV-1 diversification have yet to be examined. In this study, we conduct molecular phylogenetic analyses and mathematical modeling and reveal that stable APOBEC3H may be a critical factor in human-to-human viral transmission. This study provides evidence that stable variants of APOBEC3H potently influence HIV-1 adaptation in humans.