Maonan nationality is a relatively conservative and isolated minority in China. Little is known about the association of the Slit-Robo Rho GTPase activating protein 2 gene (SRGAP2) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese populations. This study was performed to clarify the association of the SRGAP2 rs2483058 and rs2580520 SNPs and their haplotypes with serum lipid traits in the Maonan and Han populations. Genotyping of the 2 SNPs was performed in 2444 unrelated subjects (Han, 1210 and Maonan, 1234) by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The allelic (rs2483058) and genotypic (rs2483058 and rs2580520) frequencies were different between the two ethnic groups. Four haplotypes were identified in our populations, and the rs2483058G-rs2580520C haplotype was the commonest one. The rs2483058C-rs2580520G haplotype was associated with an increased risk of dyslipidemia, and showed consistent association with serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1 levels, and the ApoA1/ApoB ratio. These results indicated that the SRGAP2 SNPs and their haplotypes were associated with serum lipid levels. Their haplotypes can explain much more serum lipid variation than any single SNP alone, especially for serum TC, HDL-C and ApoA1 levels.