Limited information is available on host genetic polymorphisms that confer resistance to HIV-1 infection in Han Chinese who persistently remain seronegative (HEPS) despite high exposure to HIV-1 through unprotected sexual activity with known HIV-1-seropositive spouses or long-term sexual partners. The aim of this study was to investigate the correlation of CCR5-Delta32, CCR2b-64I, and SDF1-3'A polymorphisms with susceptibility to HIV-1 infection through sexual transmission in Han Chinese. A cross-sectional study was used to analyze the differences in allelic frequencies of CCR5-Delta32, CCR2b-64I, and SDF1-3'A among HEPS, healthy HIV-unexposed individuals, and HIV-1-seropositive individuals. Restriction fragment length polymorphism (RFLP) analysis was used for genotype determination. The CCR5-Delta32 mutation was not detected in the three groups (n = 260). The allelic frequencies of CCR2b-64I were 21.57%, 21.63%, and 22.12% in the three groups, respectively. There was no significant difference among the three groups in CCR2b-64I distribution. The allelic frequencies of SDF1-3'A were 20.19%, 28.37%, and 29.33% in the three groups, respectively. There was a significant difference in the allelic distribution of SDF1-3'A between HEPS and healthy HIV-unexposed individuals (p = 0.023), as well as between HEPS and HIV-1-seropositive individuals (p = 0.049). Statistical analysis showed that the allelic distributions on CCR2b-64I and SDF1-3'A were in equilibrium according to the Hardy-Weinberg equation. The mutant genotypes of CCR5-Delta32 and CCR2b-64I were not correlated with HIV-1 infection through sexual transmission in Han Chinese. SDF1- 3'A was associated with a high risk of HIV-1 infection through sexual transmission in Han Chinese.