Killer immunoglobulin-like receptors (KIRs) can regulate the activation of NK and T cells in response to infection. Syphilis is a sexually transmitted infection caused by the Treponema pallidum subspecies pallidum spirochete bacterium. The objective of this study was to explore whether KIR genotypes and haplotypes were associated with syphilis in a Chinese Han population. Polymerase chain reaction with sequence-specific primers (PCR–SSP) was used to identify the KIR genotypes in 190 patients with syphilis and 192 healthy controls. The frequency of genotype P was higher in healthy controls than that in patients with syphilis (P = 0.002), and its OR was 0.304, while the frequencies of genotypes AE and AG were higher in patients with syphilis than those in healthy controls. The frequency of haplotype 17 was lower, and its OR was 0.321, whereas the frequencies of haplotype 1 and 6 were higher in patients with syphilis than those in healthy controls. KIR haplotypes A and B have distinctive centromeric (Cen) and telomeric (Tel) gene content motifs. The frequency of Tel-B/B was higher in patients with syphilis than that in healthy controls (P = 0.024). Based on these findings, it seems that individuals with the genotype AE, AG or Tel-B/B, or haplotypes 1 and 6 are susceptible to syphilis, whereas individuals with genotype P or haplotype 17 are protective from syphilis in the Chinese Han population.