In Taiwan, type 2 diabetes mellitus (T2DM) is increasing and accounts for a high proportion of medical costs. Recent genome-wide scans have mapped three diabetes susceptibility loci on chromosomes 10q25.3 and 3q27, where the transcription factor 7-like 2 gene (TCF7L2) and adiponectin gene (APM1) are located, respectively. This study aimed to explore the TCF7L2 and adiponectin gene polymorphisms in Taiwanese T2DM patients. In order to determine whether genetic polymorphisms of TCF7L2 and adiponectin are associated with T2DM, PCR-restriction fragment length polymorphism and PCR product sequencing experiments were performed to identify genetic polymorphisms in TCF7L2 rs12255372, rs7903146, and adiponectin single-nucleotide polymorphism (SNP)-45/SNP-276. We collected blood from unrelated T2DM patients and unrelated healthy controls. Our data suggest that TCF7L2 polymorphisms are rare in Taiwanese T2DM patients. Regarding the adiponectin gene SNP-45, T2DM patients with genotype TT had lower high-density lipoproteincholesterol levels than those with genotypes TG and GG (p = 0.011). Females with genotype GG had lower levels than males with genotype GG (p = 0.035). Our data show that cholesterol level might be correlated with the adiponectin SNP gene for T2DM. The adiponectin SNP might be associated with increased cardiovascular risk in T2DM patients.