Non-Hodgkin's lymphomas (NHL) are a group of malignant diseases of complex genetic and non genetic background. NHL is the tenth most common malignancy worldwide and one of the most common cancers in Oman. The increased incidence has been attributed to many factors that provoke chronic antigenic stimulation (e.g. infections, autoimmune disorders, pesticide). In addition, a number of polymorphism within some cytokines genes (IL-10 and TNF-a,) and methylenetetrahydrofolate reductase genes (MTHFR) have been implicated Methods: This study examined the association of mutations in IL-10 T-3575A, TNF-a G-308A, MTHFR C677T and MTHFR A1298C genes with pathogenesis of Diffuse Large B Cell Lymphoma (DLBCL) among Omanis. Moreover, correlation of these mutations with prognostic features and long term survival at presentation were assessed. A total of 80 patients and 115 controls were evaluable, the DNA was examined for mutations in the above genes by PCR, RFLP and sequencing. Results: Alleles and genotypes frequencies of the IL-10, TNF-a and MTHFR genes were compared between patients and controls. A slight increase in the frequency of mutant alleles of IL-10 -3575A, TNF-a -308A, MTHFR 677T and MTHFR 1298C was observed among the patients. No association between genotypes of the above genes and DLBCL was seen, except for the homozygous IL10 -3575AA (P = 0.046; OR = 3.18; 95% CI 1.020- 9.926) and heterozygous MTHFR1298 AC (P = 0.036; OR= 1.986; 95% CI 1.045 - 3.772). Correlation with presenting features revealed that TNF-a contribute to aggressive stage of the disease. The heterozygous IL10 -3575 A/T showed a trend towards shorter survival while the mutant homozygous MTHFR 1298CC genotypes showed a trend towards longer survival when analyzed with IPI status. Conclusion: Homozygous form of mutant IL-10 gene and heterozygous form of methylenetetrahydrofolate gene may be implicated in the genesis and progression of DLBCL in Omani patients. TNF-a G-308A affects prognosis of the disease. Heterozygous IL-10-3575AT predict shorter patients' survival whereas, mutant MTHFR 1298CC has a protective effect reşults in longer survival. Further validation and identification of similar genes can help in development of biomarker for diagnosis and better management of DLBCL in Oman.