In a previous study, we reported a novel single nucleotide polymorphism (SNP) 698C>T (P233L) in the gene, C5L2. This gene has been demonstrated to encode a functional receptor of acylation-stimulating protein (ASP), a G-protein-coupled receptor (GPCR), that has been shown to influence insulin secretion in cultured pancreatic islet cells in vitro and is a stimulator of triglyceride synthesis and glucose transport in vivo. In this study, we evaluated the relationship between this novel C5L2 SNP and development of type 2 diabetes mellitus (T2DM) in the Chinese Han population. A case-control study examining Chinese Han T2DM patients (n = 554) and healthy controls (n = 648) was performed to investigate the role of the 698C>T (P233L) C5L2 polymorphism. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to determine expression of this SNP. Heterozygote carriers of the 698CT C5L2 genotype were more frequent among T2DM patients (13.5%) than controls (3.2%; P < 0.001). The frequency of 698CT heterozygote carriers was significantly higher in women (12.8%) than in male subjects (5.7%, P < 0.001). The odds ratio (OR) of T2DM for 698CT carriers was 4.675 [95% confidence interval (CI) 2.840-7.694]. After adjustment of confounding factors such as age, sex, smoking, drinking, hypertension, and triglyceride (TG), total cholesterol, high-density lipoprotein, and low-density lipoprotein levels, the difference remained significant (P < 0.001, OR 5.556, 95% CI 2.444-12.630). Furthermore, the diabetic 698CT carriers displayed an increase in their serum TG level. However, there were no significant differences observed in any of the parameters measured in the control group. We conclude that the 698CT genotype of C5L2 may be an influencing genetic factor for T2DM in the Chinese Han population. These findings also indicate that heterozygous expression of 698CT C5L2 may contribute to metabolic abnormalities.