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Benzene reactive metabolites can lead to DNA damage and trigger the p53-dependent defense responses to maintain genomic stability. We hypothesized that the p53-dependent genes may play a role in the development of chronic benzene poisoning (CBP). In a case-control study of 303 patients with benzene poisoning and 295 workers occupationally exposed to benzene in south China, we investigated associations between the risk of CBP and polymorphisms in three p53-dependent genes. Potential interactions of these polymorphisms with lifestyle factors were also explored. We found p14ARF rs3731245 polymorphism was associated with risk of CBP (P = 0.014). Compared with those carrying the GG genotype, individuals carrying p14ARF rs3731245 GA+AA genotypes had a reduced risk of CBP ([adjusted odds ratio (ORadj) = 0.57, 95%CI = 0.36–0.89]. Further analysis showed p14ARF TGA/TAG diplotype was associated with an increased risk of CBP (P = 0.0006), whereas p14ARF TGG/TAA diplotype was associated with a decreased risk of CBP (P = 0.0000001). In addition, we found individuals carrying both MDM2 Del1518 WW genotype and p14ARF rs3731245 GA+AA genotypes had a lower risk of CBP (ORadj = 0.25; 95%CI = 0.10–0.62; P = 0.003). Although these results require confirmation and extension, our findings suggest that genetic polymorphisms in p14ARF may have an impact on the risk of CBP in the study population.