Patients with primary central nervous system lymphoma (PCNSL) have a prognosis poorer than that of systemic lymphoma patients . In patients with this condition, TLR4/STAT3 pathway alterations and the MYD88 L265P mutation may be viable targets for therapeutic intervention . The present study was, therefore, designed to identify clinicopathologic correlates of MYD88 mutations and TLR4/STAT3 pathway alterations in PCNSL . We detected TLR4 and p-STAT3 in 41.5% (22/53) and 43.4% (23/53) of PCNSL patients, respectively, while 60.4% of these patients (32/53) were found to harbor the MYD88 L265P mutation . TLR4 expression was found to be significantly associated with the presence of multiple brain lesions, while p-STAT3 expression was significantly linked to advanced age, the presence of multiple brain lesions, non-GCB histological findings, and non-CR status . The presence of the MYD88 L265P mutation was significantly linked to advanced age, the presence of multiple brain lesions, and DLBCL molecular subtype . Multivariate analyses additionally confirmed that elevated TLR4 and p-STAT3 expression levels are associated with a poorer PCNSL patient prognosis . Based on these findings, we hypothesize that signaling through the TLR4/MYD88/STAT3 pathway plays a key role in the pathogenesis of PCNSL.