BACKGROUND: Non-Hodgkin Lymphoma (NHL) is an increasingly prevalent hematological malignancy in Egypt, highlighting the need for a better understanding of its genetic risk factors. The TP53 and MDM4 genes play critical roles in cellular homeostasis and cancer development. This study aimed to assess the frequency of the TP53 (SNP rs1042522) Arg72Pro and MDM4 (SNP rs4245739) A > C polymorphisms as potential risk factors for NHL in adult Egyptian patients. METHODS: A case-control study was conducted involving 80 adult NHL patients and 100 control age- and sex-matched healthy controls. Genotyping for the TP53 (rs1042522) Arg72Pro and MDM4 (rs4245739) A > C polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: A significant association was found between the homozygous TP53 Pro/Pro genotype and increased susceptibility to NHL (47.5% in patients vs 4.0% in controls; P < .001), as well as a higher frequency of the mutant C allele among NHL cases (63.8% vs 28.0%; P < .001). In contrast, no significant association was observed between MDM4 polymorphisms and NHL risk. In addition, analysis of treatment outcomes revealed no statistically significant differences in overall survival or progression-free survival based on TP53 or MDM4 genotypes. CONCLUSIONS: These findings suggest that the TP53 Arg72Pro polymorphism is a significant genetic marker for NHL susceptibility in the Egyptian population, while MDM4 polymorphisms do not appear to contribute to disease risk. Further studies are warranted to elucidate the genetic mechanisms underlying NHL and to explore their implications for risk stratification and therapeutic strategies.