The p14(ARF)/MDM2/p53 pathway plays an important role in modulation of DNA damage and oxidative stress responses. The aim of this study was to determine whether genetic variants in MDM2 and p14(ARF) are associated with risk of salivary gland carcinoma (SGC).Four single nucleotide polymorphisms (SNPs) in MDM2 and p14(ARF) (MDM2-rs2279744, MDM2-rs937283, p14(ARF)-rs3731217, and p14(ARF)-rs3088440) were genotyped in 156 patients with SGC and 511 cancer-free controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).MDM2-rs2279744 was significantly associated with a moderately increased risk of SGC (OR, 1.5, 95% CI, 1.1-2.2). There was a trend toward significantly increased SGC risk with increasing number of risk genotypes of the four polymorphisms (P(trend) = 0.004). Individuals carrying 3-4 risk genotypes in MDM2 and p14(ARF) were at increased SGC risk (OR, 2.0, 95% CI, 1.1-2.7) compared with individuals carrying 0-2 risk genotypes. Moreover, the combined effect of risk genotypes of MDM2 and p14(ARF) was more pronounced among young subjects (≤ 45 years), female subjects, subjects with race/ethnicity other than non-Hispanic white, ever-smokers, and ever-drinkers.Our results support the involvement of SNPs of MDM2 and p14(ARF), either alone or more likely in combination, in susceptibility to SGC. Larger studies are needed to validate our findings.