This study investigated the association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels in the population of Southwest China. Genotyping of 12 SNPs (i.e., rs2238675, rs2228603, rs58542926, rs735273, rs16996148, rs968525, rs17216525, rs12610185, rs10401969, rs8102280, rs73001065 and rs150268548) was performed in 1248 hyperlipidemia patients and 1248 normal subjects. The allelic and genotypic frequencies of the detected SNPs differed substantially between the normal and hyperlipidemia groups (P < 0.05-0.001), and the association of the 12 SNPs and hyperlipidemia was also observed (P < 0.004-0.0001). Four haplotypes (i.e., NCAN C-C, CILP2 G-T, PBX4-SUGP1 G-C, and MAU2 C-A-G-T) and 5 gene-gene interaction haplotypes (i.e., rs2238675C-rs2228603C, rs16996148G-rs17216525T, rs12610185G-rs10401969C, rs73001065G-rs8102280A-rs150268548G-rs968525C and rs73001065C-rs8102280A-rs150268548G-rs96852)showed a protective effect, whereas four other haplotypes (i.e., TM6SF2 T-A, TM6SF2 C-A, MAU2 G-G-G-C and MAU2 C-G-A-T), as well as 4 gene-gene interaction haplotypes (i.e., rs58542926C-rs735273A, rs58542926T-rs735273A, rs73001065G-rs8102280G-rs150268548G-rs968525C, and rs73001065C-rs8102280G-rs150268548A-rs968525T), exhibited an inverse effect on hyperlipidemia (P < 0.05-0.0001). There were notable three-locus models comprising SNP-SNP, SNP-environment, and haplotype-haplotype interactions (P < 0.05-0.0001). The individuals with some genotypes and haplotypes reduced the prevalence of hyperlipidemia, whereas the individuals with some other genotypes and haplotypes augmented the prevalence of hyperlipidemia. The NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions on hyperlipidemia were observed in the population of Southwest China.