Aims The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomized controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has shown to significantly improve survival. An in vitro study has revealed that mTOR is activated in esophageal squamous cell carcinoma (ESCC) cell lines and that mTOR expression is inhibited by rapamycin. The objectives of this histological study were to determine the proportion of ESCC tissues with activated mTOR (p-mTOR) expression, thereby assessing the percentage of patients with ESCC that would possibly benefit from neoadjuvant rapamycin therapy and to identify the clinicopathologic features of these potentially rapamycin-sensitive tumours. Methods The expression of p-mTOR (Ser2448) was immunohistochemically assessed in a validated tissue microarray comprising triplicate tissue biopsy cores of 108 formalin-fixed, paraffin-embedded ESCCs. Staining results were correlated with clinicopathologic data. Results Normal esophageal epithelium was negative for p-mTOR. Activated mTOR expression was located in the cytoplasm of esophageal tumor cells. Twenty-six (25%) of 105 assessable ESCCs showed tumour cells with positive staining for p-mTOR. Activated mTOR expression was only associated with a lesser degree of differentiation (P=0.024). No correlation was detected between p-mTOR and the proliferation marker Ki-67. Conclusions Activated mTOR can be detected in one quarter of ESCCs. Since this subset of patients may potentially benefit from mTOR inhibiting therapy, a phase II clinical trial of neoadjuvant mTOR-inhibiting therapy in patients with ESCC may be considered.