We hypothesized that the polymorphisms in the two p53 family genes (p53 Arg72Pro and p73 G4C14-to-A4T14 at exon 2 (G4A)) and p21 Ser31Arg polymorphism might modulate the risk of non-Hodgkin's lymphoma, and conducted a hospital-based prevalent case control study at Aichi Cancer Center Hospital to clarify the association. Risk estimation for each genotype by the unconditional logistic model demonstrated the possible association between the p53 Pro72 allele and the risk of non-Hodgkin's lymphoma in Japanese population (OR = 1.59; 95% CI, 0.99-2.57, P = 0.057), although no other significant association was observed. The analyses of statistical interactions between these three polymorphisms (p73 G4A, p53 Arg72Pro and p21 Ser31Arg polymorphisms) revealed the marginally significant OR for interaction between p53 Arg72Pro and p73 G4A polymorphisms (OR = 2.54; 95% CI, 0.97 6.62, P = 0.057). When those without p53 Pro72 and p73 A4T14 alleles were defined as a reference, those with p53 Pro72 and p73 A4T14 alleles demonstrated a significantly higher OR (2.08; 95% CI, 1.11-3.90, P = 0.023). Further examination with a sufficiently larger population and other ethnicities are required to confirm our findings.