Objective: To discuss the predictive value of enhancer of zeste homolog 2 (EZH2) in the treatment of diffuse large B-cell lymphoma (DLBCL) with RCHOP regimen. Methods: A total of 80 patients with DLBCL treated with RCHOP regimen in our hospital from January 2017 to May 2018 were selected. The relationship between EZH2 expression and therapeutic effect was analyzed. The ROC curve of EZH2 predicting therapeutic effect was made. The relationship between pCR and pathological characteristics was discussed. Results: Among 80 patients, 49 had high expression of EZH2, 31 had low expression of EZH2, and 51.25% had pCR in DLBCL patients treated with RCHOP. The complete response (CR) and objective response rate (ORR) in patients with high expression of EZH2 were significantly lower than those in patients with low expression of EZH2 (P<0.05). The predictive effect of EZH2 was 0.874 (P<0.05). There was no correlation between pCR and sex, age, Eastern Cooperative Oncology Group (ECOG) score, International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) factor (P>0.05), but there was correlation between pCR and Hans typing and EZH2 expression level (P<0.05). Conclusion: The low expression of EZH2 in DLBCL patients is a predictor of high pCR rate after RCHOP treatment. It is helpful to provide better guidance for clinical treatment of DLBCL patients.