Acute myocardial infarction is a highly prevalent cardiovascular disease in Taiwan. Among several etiological risk factors, obesity and inflammation are strongly associated with the frequency of hypertension, cardiovascular disease, diabetes, and myocardial infarction. To discriminate obesity- and inflammation-related genes and the onset of acute myocardial infarction (AMI), a case-control study was conducted to investigate the association of the -308G/A polymorphisms of tumor necrosis factor (TNF)-alpha and the C825T polymorphism of guanidine nucleotide binding protein 3 (GNB3) with the onset of AMI among Taiwanese cohorts. A total of 103 AMI patients and 163 matched normal control samples were enrolled in the present study. The genomic DNA was extracted and subjected into polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. An association between the A homozygosity of the TNF-alpha-308G/A polymorphism and the onset of AMI was observed among the male subjects (p = 0.026; Spearman index = 0.200, p = 0.008). An association between the T homozygosity of GNB3 C825T polymorphism and obesity was also observed (Fisher's exact, p = 0.009). The TT genotype has a protective effect against acquiring AMI among the obese female population in Taiwan (Fisher's exact, p = 0.032). In conclusion, TNF-alpha-308G/A and the GNB3 C825T polymorphisms are associated with obesity and AMI in the Taiwanese population.