The protein product of the murine double minute gene 2 (MDM2) negatively controls the work of the p53 protein and the retinoblastoma protein (pRB). Recent studies have found that MDM2 expression correlates with chemoresistance of tumor cells. In the present study, the correlation between MDM2 expression and chemoradioresistance was evaluated in patients with esophageal squamous cell carcinoma (ESCC). The immunoreactivities of p53, pRB, and MDM2 were evaluated in 148 surgically resected ESCC by using monoclonal antibodies. The disease-free survival of 107 surviving patients who underwent curative surgery was compared among groups with positive and negative expressions of p53, pRB, and MDM2. High immunoreactivities of p53, pRB, and MDM2 were detected in 47.3%, 64.2%, and 32.4% of cases, respectively. In 107 patients undergoing curative surgery, pRB losses and MDM2 overexpression were found to be poor prognostic factors by univariate analysis. In multivariate analysis, only MDM2 expression was determined to be a prognostic factor independent of the tumor stage. Moreover, we found that MDM2 expression correlates with short survival of patients undergoing postoperative adjuvant chemoradiotherapy. In patients without adjuvant therapy, however, the MDM2 status did not correlate with patient survival. The present results indicate that MDM2 expression may be not only a prognostic marker for patients with ESCC, but also a novel marker for predicting a lack of response to chemoradiotreatment.