The relationship among the single nucleotide polymorphisms (SNPs) of the C-X-C motif chemokine ligand 12 gene (CXCL12) and the serum lipid profiles in the Chinese population has rarely been described, especially in somewhat old-fashioned and isolated Maonan minority. The goal of the current study was to elucidate the connection among the CXCL12 rs501120 and rs1746048 SNPs, haplotypes, several environmental factors and serum lipid traits in the Maonan as well as Han populations. Genotyping of the two SNPs, gel electrophoresis and direct sequencing were accomplished in 1,494 distinct subjects (Maonan, 750 and Han, 744) using polymerase chain reaction and restriction fragment length polymorphism. The frequencies of genotypes as well as alleles of the two SNPs were not similar between the two ethnic groups. The rs501120 SNP was related with serum total cholesterol levels, while the rs1746048 SNP was related with serum apolipoprotein (Apo) B levels. Four haplotypes were identified, of which the rs501120A-rs1746048C haplotype was the most common. The haplotypes of rs501120A-rs1746048T increased and rs501120G-rs1746048C decreased the risk of hyperlipidemia (P < 0.001 for each), showing consistent association with the levels of serum triglyceride, ApoA1 and ApoB. These outcomes specify that the CXCL12 SNPs as well as their haplotypes are related to serum lipid levels. Different serum lipid levels between both populations may partially be related to the CXCL12 SNPs, their haplotypes along with several environmental factors.