Background: Chronic obstructive pulmonary disease (COPD) is a multifactorial disease influenced by genetic and environmental factors, particularly cigarette smoking. Although cigarette smoke may be directly mutagenic, polymorphisms in the genes controlling acquired somatic mutations may also contribute, at least to some extent, to the observed differing susceptibilities to COPD. To investigate the involvement of genetic polymorphisms of p53 and p21 in the pathogenesis of COPD, the authors performed a case-control study involving 206 subjects with COPD and 210 healthy smokers as control subjects. Methods: Polymorphisms of p53 and p21 genes were analyzed using the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique on genomic DNA isolated from peripheral lymphocytes. The distribution of the p53 and p21 polymorphisms in healthy subjects and COPD patients was examined and compared using the Pearson X2 test. Significance was accepted at P < 0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) of each specific genotype were calculated using logistic regression analysis to quantitatively assess the degree of association observed. Results: The distribution frequencies of genotypes of p53 codon 72 and p21 codon 31 were significantly different between the COPD and the control groups. Higher ORs for COPD were seen for persons with p53 Pro/Pro or Pro/Arg genotypes against Arg/Arg genotype [OR = 2.35, 95% CI 1.27–4.39, P = 0.008], or p21 Arg/Arg and Arg/Ser genotypes against Ser/Ser genotype [OR = 2.07, 95% CI 1.06–4.05, P = 0.033]. Conclusions: The polymorphisms of p53 and p21 were significantly associated with the occurrence of smoking-related COPD in Taiwan Chinese patients.