Single nucleotide polymorphisms (SNPs) in the p53, MDM2 and p21 genes of the p53 pathway have been extensively studied. The main aim of the current retrospective study was to evaluate the possible predictive value of SNPs in the p53 pathway in locoregionally advanced nasopharyngeal carcinoma (NPC) in response to radiotherapy. In total, 75 consecutive patients with locoregionally advanced NPC were enrolled. Three SNPs in the p53 pathway were identified using the Sanger sequencing method from retrospectively collected paraffin-embedded biopsy specimens. The effects of genetic polymorphisms on patient progression‑free survival (PFS) were analyzed using the Cox proportional hazards model, Kaplan-Meier method and log-rank test. All of the selected subjects completed questionnaires on smoking habits prior to treatment. Multivariate analysis showed that the p53 codon 72 Pro/Pro genotype [hazard ratio (HR), 0.300; 95% confidence interval (CI), 0.092-0.983; P=0.047] and heavy smoking (≥30 pack-years) (HR, 2.899; 95% CI, 1.349-6.229; P=0.006) are independent significant prognostic factors for PFS in patients with locoregionally advanced NPC. Moreover, mean times to disease progression for heavy smokers (≥20 pack-years) carrying p53 codon 72 Arg/Arg, p21 codon 31 Arg/Arg and MDM2 309 SNP G/G genotypes were only 14.78 ± 3.00, 11.00 ± 0.58 and 11.17 ± 1.85 months, respectively. These time scales were less than half of those recorded for patients containing other genotypes and moderate smokers (<20 pack-years). In conclusion, the p53 codon 72 polymorphism is an independent prognostic marker for locoregionally advanced NPC. Moreover, analysis of SNPs in the p53 pathway may facilitate the identification of patients at high risk of poor disease outcome in subgroups of heavy smokers.