In the present study, the expression of p53, mouse double minute 2 homolog (MDM2), eukaryotic translation initiation factor 4E (eIF4E), and epidermal growth factor receptor (EGFR) were investigated in nasopharyngeal carcinoma (NPC), and the correlation between their expression and clinicopathological characteristics and prognosis was analyzed. The medical records of 96 NPC patients who had undergone biopsy prior to radical radiotherapy and chemotherapy between 2005 and 2009 were reviewed, retrospectively. All patients received intensity-modulated radiotherapy with concurrent platinum-based chemotherapy. Patients were followed-up for three years. Streptavidin-peroxidase immunohistochemistry was used to evaluate the expression of p53, MDM2, eIF4E and EGFR in NPC biopsy specimens, and the association between their expression and clinical parameters and survival was analyzed. The p53, MDM2, eIF4E and EGFR expression rates were 65.6% (63/96), 79.16% (76/96), 77.08% (74/96) and 89.5% (86/96), respectively. p53 ((2),20.322; P=0.001) and EGFR ((2),8.337; P=0.005) expression were found to correlate with T stage, whereas MDM2 ((2),16.361; P=0.001) expression was found to correlate with lymph node metastasis. p53 expression was found to inversely correlate with MDM2 expression (r, -3.24; P<0.05). Three-year survival rates were lower in p53-positive (76.2%) patients when compared with p53-negative (93.9%) patients. In addition, three-year survival rates were lower in EGFR-positive (75.8%) patients than in EGFR-negative patients (91.2%). The Cox proportional-hazards regression model revealed that p53 (,-0.455; (2),5.491; P=0.019) and EGFR (, 3.93; (2), 11.95; P=0.001) expression were independent prognostic factors. Thus, it was hypothesized that p53 and EGFR expression present potential unfavorable prognostic markers for patients with NPC.