Several studies have confirmed that signal transducer and activator of transcription 3 (STAT3) is constitutively phosphorylated in primary central nervous system lymphoma (PCNSL). However, the underlying mechanism and prognostic significance of STAT3 activation have not been clarified. The expression of STAT3, phosphorylated STAT3 (p-STAT3) and interleukin-10 (IL-10) was examined in 32 PCNSL samples by immunohistochemistry (IHC). The relationship between IL-10 expression and STAT3 phosphorylation was determined. In addition, the associations of the expression of these proteins with clinical factors and survival were analyzed. Expression of STAT3, p-STAT3 and IL-10 was detected in 28 (87.5%), 17 (53.1%) and 25 (78.1%) samples, respectively; IL-10 expression was significantly associated with STAT3 phosphorylation in PCNSL (P = 0.033). STAT3 phosphorylation and IL-10 expression were associated with the presence of multiple brain lesions (P = 0.004 and P = 0.027, respectively), suggesting that STAT3 activation may enhance the intracranial spread of tumors in PCNSL. The 2-year overall survival (OS) and progression-free survival (PFS) rates were 67.8% and 35.5%, respectively. Kaplan-Meier survival analysis demonstrated that STAT3 phosphorylation, IL-10 expression and multiple brain lesions were significantly associated with PFS in PCNSL (P = 0.009, P = 0.030 and P = 0.040, respectively). However, Cox regression analysis indicated that only STAT3 phosphorylation was significantly associated with a shorter PFS (P = 0.016, HR: 3.22, 95%CI: 1.24-8.37). Our results indicate that STAT3 activation is closely related to IL-10 expression and that p-STAT3 may be a novel biomarker predicting poor survival in PCNSL. Copyright © 2019 Elsevier Inc. All rights reserved.