Germline polymorphisms of genes involved in different steps of tumorigenesis like p53, the tumor suppressor gene, are reported to determine the individual susceptibility to cancer. Lung cancer is one of the most common and lethal cancers and tobacco smoking remains its most important etiologic factors. The most frequently p53 mutated codons of lung cancer are 72 (exon 4) and 249 (exon 7). Since mutations in the p53 gene are present in ∼40% of all human lung cancers and are more common in smokers than in nonsmokers, we aimed to detect the status of p53 at codon 72 for Arg/Arg or Arg/Pro or Pro/Pro allele polymorphism and p53 codon 249 mutation in smokers and nonsmokers of South India. Allele frequencies in the nonsmokers were 0.16 for the Arg/Pro allele and 0.84 for the Pro/Pro allele in our study population. Among the smokers, the frequencies of the Arg/Pro, Arg/Arg, and Pro/Pro alleles were 0.88, 0.04, and 0.08, respectively. No mutation was detected in both smokers and nonsmokers in p53 codon 249. From the worldwide scenario, it can be speculated that the smokers, with Arg/Pro genotype are more prone for lung cancer or to other types of cancer.