Genetic polymorphisms of p53 codon 72 are thought to have significant effects on the metabolism of environmental carcinogens and thus on lung cancer risk, but the reported results are not always consistent. The aim of this study is to investigate the relationship between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population. A population-based control study was conducted in 360 lung cancer patients and 360 cancer-free controls. The genotype of the p53 codon 72 was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Patients with lung cancer had a significantly lower frequency of Pro/Pro genotype [odds ratio (OR) = 0.58, 95 % confidence interval (CI) = 0.40, 0.84; P = 0.004] and Pro allele (OR = 0.72, 95 % CI = 0.59, 0.89; P = 0.002) than controls. Patients with squamous cell carcinoma had also a significantly lower frequency of Pro/Pro genotype (OR = 0.45, 95 % CI = 0.25, 0.82; P = 0.009). In the analysis combining p53 codon 72 polymorphisms and smoking, smokers who had smoked for more than 30 pack-years had a significantly lower frequency of Pro/Pro genotype (OR = 0.52, 95 % CI = 0.30, 0.92; P = 0.03) compared with non-smokers. This study suggests that p53 codon 72 polymorphisms play a role in the development of lung cancer and modifies the risk for smoking-related lung cancer in a Chinese population.