Aim To investigate the correlation of cysteine aspartic acid specific protease 8 (CASP8) gene －652 6N insertion/deletion (I/D) polymorphisms with hyperlipidemia. Methods CASP8 gene －652 6N I/D polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing in 350 controls and 357 patients with hyperlipidemia in Sichuan area. Results The I/I, I/D and D/D genotype frequencies were 54.3%, 41.4%, 4.3% in control group and 55.2%, 36.1%, 8.7% in hyperlipidemia group, respectively.The genotype frequency distribution between the two groups showed significant differences (P＝0.038). However, no significant difference of I and D allelic frequency was found between the two groups. Compared with the CASP8 gene －652 6N I/I or the combined I/I＋I/D genotype, a significant increased risk of hyperlipidemia was found for the D/D genotype people (OR＝1.3,5%CI was 1.043~3.810, P＝0.034 and OR＝2.4,5%CI was 1.125~4.008, P＝0.018, respectively). What's more, the triglyceride in serum of D/D genotype people was strikingly higher than that in I/D and I/I genotype people. Conclusion These findings indicate that CASP8 gene －652 6N I/D polymorphisms are associated with hyperlipidemia in Sichuan area, and D/D genotype could increase the risk of hyperlipidemia.