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Introduction Chronic obstructive pulmonary disease (COPD) is a chronic systemic inflammatory disease characterized by progressive airflow obstruction. Increased concentrations of tumor necrosis factor (TNF)-α have been found in induced sputum, [...], The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case-control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-α gene promoter region at -308, -863, and -1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-α levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The--863 CA genotype was associated with a better [FEV.sub.1]/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/[m.sup.2], p = 0.048). In addition, COPD patients with the -1031 C carrier genotype had higher serum TNF-α levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74-0.96, p = 0.008) was the only independent predictor for mortality. The TNF-α -863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers. Keywords TNF-α * Genetic polymorphism * COPD * Pulmonary function parameter