Objective To investigate protocadherin 10 (PCDH10) methylation at promoter 5’-cytosine-phosphoric acid-guanine motif (CpG) island as a tool for non-invasive diagnosis and prognosis evaluation of primary gastric cancer. Methods Real-time fluorescent quantitative methylation specific polymerase chain reaction (Real-time MSP) technique was used for detection of PCDH10 promoter methylation in both tissue and serum specimens from 202 gastric cancer (GC), 52 gastric epithelial dysplasia, and 68 chronic gastritis, as well as 120 healthy human serum specimens. The relationship between PCDH10 methylation with clinicopathological parameters and prognosis was analyzed. Results The incidence of PCDH10 methylation in gastric cancer tissues (80.2%, 162/202) was significantly higher than that in paired adjacent tissues (26.7%, 54/202), gastric epithelial dysplasia (23.1%, 12/52) and chronic gastritis specimens (14.7%, 10/68) (all P=0.000). Detectable rate of PCDH10 methylation in serum specimens was in good agreement with that in the paired tumor tissues, with the Aζ value being 0.862 (P=0.000). The level of PCDH10 methylation in serum was closely correlated to age at diagnosis (P=0.018), H. pylori (Hp) infection (P=0.000), tumor size (P=0.000), tumor differentiation (P=0.002), lymphatic invasion (P=0.000), venous invasion (P=0.007), invasion depth (P=0.000), lymphatic metastasis (P=0.000), distant metastasis (P=0.015), clinical stages (P=0.000) and poor prognosis (P=0.000), but not with gender (P=0.435), tumor site (P=0.458) and growth pattern (P=0.435). Conclusion PCDH10 methylation plays an important role in the tumorigenesis and development of gastric cancer. Key words: Gastric cancer; Protocadherin 10; DNA methylation; Early diagnosis; Prognosis