Background: Gastric cancer (GC) with peritoneal metastasis has an extremely poor prognosis. Paclitaxel (PTX) intraperitoneal infusion provides an effective treatment for these patients. However, GC patients with peritoneal metastasis who receiving PTX treatments tend to occur PTX-resistance accompany with more aggressive ascites and metastasis. How does this happen is still unknown. Here, we aimed to explore the mechanisms that mediate PTX-resistance and metastasis in GC with peritoneal metastasis. Methods: Ascites samples were collected before PTX infusion and after the relapse in 3 GC patients. To determine the expression of significantly changed proteins, we performed tandem mass tag (TMT) quantitative proteomics. Immunohistochemistry (IHC) staining and western blot were performed to confirm the expression of CDH11 in the PTX-resistant tissues and MKN45P-PR cells. Invasion and migration of GC cells were examined by in vitro transwell and wound healing assays and in vivo dissemination experiments. Results: CDH11 expression was downregulated in the relapsed PTX-resistant ascites, tissues and the PTX-resistant cell line MKN45P-PR. Inhibition of CDH11 expression promoted the invasion, migration and PTX resistance of MKN45P cells, while overexpression of CDH11 repressed these biological functions. Moreover, tumors disseminated in the mice peritoneal cavity induced by MKN45P-PR cells and shCDH11 cells displayed higher metastatic ability and resistance to PTX treatment. Conclusions: Our results reveal that CDH11 is inhibited in the relapsed PTX-resistant patients and the downregulated CDH11 expression promotes GC cell invasion, migration and PTX resistance. CDH11 may have the potential to serve as a predictable marker for the occurrence of PTX resistance in GC patients with peritoneal metastasis.