Background: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL), is characterized by clinical and molecular heterogeneity. MYD88 L265P mutation is a major driver mutation with significant diagnostic, prognostic, and therapeutic implications and has been extensively studied in multiple populations. However, its prevalence and clinical relevance in our cohort remain to be fully investigated. Objective: This study aimed to determine the frequency of the MYD88 L265P mutation in patients with B-cell neoplasms, particularly those with DLBCL and its association with laboratory and clinical parameters as well as its potential association with disease progression. Patients and methods: This prospective study was conducted on 123 individuals (63 B cell neoplasms & 60 healthy controls). MYD88 L265P mutation was detected using polymerase chain reaction (PCR) techniques. DLBCL patients were classified according to MYD88 mutation status and subgroup analysis was performed. Results: The MYD88 L265P mutation was detected exclusively in 17% of DLBCL cases (n = 8). According to subgroup analysis, beta-2 microglobulin (B2M) levels were substantially higher in MYD88-mutated DLBCL patients than in the wild-type group (p = 0.005). MYD88-mutated individuals had more advanced disease (stage IV represent 37.5% vs. 17.9% in wild-type group), presence of extra nodal involvement (50% vs. 23.1 % in wild-type group) and high IPI score (50% vs. 17.9% in wild type group). The MYD88 L265P mutation was found to be an independent predictor of both progression-free survival (HR 16.543, p=0.001) and overall survival (HR 17.538, p=0.007) by multivariate analysis. Conclusion: The MYD88 mutation can be considered as an important biomarker that has impact on the prognosis and course of treatment for DLBCL patients, which suggests that MYD88 L265P might be a target for risk assessment and response to treatment.