Objective To explore the prognostic significance of p53 mutation protein in patients with diffuse large B-cell lymphoma for the purpose of individualized therapy. Methods Newly diagnosed 62 cases were randomly chosen from our hospital, p53 mutation protein and CD10, bcl-6, MUM1 were tested by immunohistochemistry. Correlation of p53 mutation protein with patients ' characteristics, genotype and survival were analysed in the study. Results p53 mutation protein was found in 48.4 % (30/62) of patients.Its expression was only related to initial treatment response (x2 =20.365, P =0.040), including complete remission rate of 33.3 % (10/30) in positive group and 59.4 % (19/32) in negative group, and non-germinal center genotype (x2=31.023, P =0.021) with 83.3 % in positive group and 56.2 % in negative group. No other correlation was not verified with clinical features. Multivariate survival analysis showed that p53 mutation protein was an independent predictor for shorter progress-free and overall survival in positive group (x2 =30.784, P =0.005 and x2 =35.276, P =0.006). Conclusion p53 mutation protein should be an independent predictor with poor prognosis and to direct personalized therapy.