BACKGROUND Although platinum-based chemotherapy is the most effective strategy for esophageal cancer, toxicity and drug resistance limit the dose administration and the application of chemotherapy. Capilliposide C (CPS-C) is isolated from the Chinese herb Lysimachia capillipes Hemsl and is approved to be effective against carcinomas. However, the activity of CPS-C against esophageal cancer remains unclear. The present study was conducted to assess the chemosensitizing effects of CPS-C for enhancing the therapeutic efficacy of oxaliplatin in esophageal squamous carcinoma cells and explore the underlying mechanism. MATERIAL AND METHODS Human esophageal squamous cell carcinoma (ESCC) TE-1 and TE-2 were used. Several in vitro and in vivo analyses were carried out, including MTT, Annexin V/PI, Western blot, and TUNEL and immunohistochemistry in a xenograft model. RESULTS CPS-C significantly enhanced the proliferative inhibition and apoptotic effect of oxaliplatin in ESCC cells. Oxaliplatin combined with CPS-C decreased the expressions of PI3K, phospho-Akt, phospho-mTOR, Bcl-2, and Bcl-XL, and increased the expression of Bax and caspase-3 significantly compared to oxaliplatin-only treatment. Furthermore, in the ESCC xenograft model, CPS-C significantly enhanced the anti-cancer effects and apoptosis of oxaliplatin. CONCLUSIONS The results indicated that CPS-C enhanced the anti-proliferative and apoptotic effect of oxaliplatin by modulating the PI3K/Akt/mTOR pathway on ESCC in vitro and in vivo.