To investigate the role that DC-SIGN neck-region length variation plays in HIV-1 transmission, we studied 530 HIV-1-positive and 341 HIV-1-negative individuals in China. The carrier frequency of a DC-SIGN allele with <5 repeat units in the neck-region was 0.9% in HIV-1-positive and 3.8% in HIV-1-negative individuals (P=.007), an observation suggesting that this DC-SIGN variation plays a role in HIV-1 transmission. These naturally occurring DC-SIGN neck-region variants were significantly more frequent in the Chinese population than in the US population (P <.001) and in a worldwide population (P=.006).