Several clinically relevant molecular classifiers of diffuse large B-cell lymphoma (DLBCL) have recently been demonstrated in Western populations. However, substantial molecular differences have recently been shown between tumors derived from different ethnic groups. To investigate prevalence and interrelationship of recently suggested molecular prognostic markers in Middle East DLBCL, we analyzed coexpression of CD10/Bcl6 (by immunohistochemistry), t(14;18) translocations (by fluorescence in situ hybridization), and methylation of the gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) in a series of 190 DLBCL patients from Saudi Arabia with clinical follow-up data. Coexpression of CD10/Bcl6 (germinal center-like immunophenotype) was found in 13%, t(14;18) translocations in 17.9%, and MGMT methylation in 75.9% of cases. There was a trend toward better prognosis (although statistically insignificant) in tumors with coexpression of CD10/Bcl6. MGMT methylation were significantly related to good prognosis. The combined analysis of both parameters revealed that MGMT methylation was independent of immunophenotype and remained a significant predictor of prognosis in nongerminal center-like DLBCL subgroup. t(14;18) was significantly associated with CD10/Bcl6 coexpression (46.7%) but infrequent in CD10-/Bcl6-negative lymphomas (9.4%; P = .0073). However, t(14;18) was unrelated to clinical outcome. In summary, our data suggest a strong prognostic importance of MGMT methylation independent of DLBCL immunophenotype. Based on previous data from Western patients, the rate of MGMT hypermethylation was higher, and the portion of germinal center-like DLBCL was lower than expected. These results provide evidence for molecular differences between Saudi Arabian and Western DLBCL.