Background: Effective and convenient early detection methods are still lack for gastric cancer. Liquid biopsy, by detecting cell-free DNA (cfDNA) methylation, circulating tumor DNA (ctDNA) mutation, and serum protein markers etc., may provide a non-invasive method to early detect cancer. However, head-to-head comparison of these biomarkers have not been studied. Here, we report the results of the Assessment of Early-Detection Based on Liquid Biopsy in Gastric Cancer (ASCEND-GASTRIC, NCT05224596), a case-control study to early detect gastric cancer via cfDNA methylation, ctDNA mutation, and pre-specified serum protein markers. Methods: Blood samples from gastric cancer patients were prospectively collected from the Department of General Surgery of Zhongshan Hospital, Fudan University. Blood samples from age-matched healthy controls were also prospectively collected. Blood samples were subjected to a methylation panel of ~490,000 CpG sites sequenced by the ELSA-seq, a mutation panel of ultra-deep sequenced 168 genes, and tumor protein assays. All blood samples (cancer, n=134; healthy control, n=330) were randomly assigned into the training and the test sets. Results: In the training set, cfDNA methylation and ctDNA mutation efficiently discerned cancer patients from healthy controls, while the commonly used protein markers of gastric cancer were not significantly higher in the cancer patients than in the healthy controls. In the test set, cfDNA methylation achieved 65.6% sensitivity (95% confidence interval [CI], 52.5%‒77.1%) at 96.8% specificity (95% CI, 89.9%‒100%), while ctDNA mutation exhibited lower sensitivity of 16.5% (95% CI, 9.1%‒26.5%) at 95.9% specificity (95% CI, 86.0%–99.5%). On top of the methylation-based model, the mutation-based model slightly increased sensitivity (70.7%; 95% CI, 57.3%‒81.9%) at the cost of reduced specificity (91.8%; 95% CI, 80.4%‒97.7%). Conclusions: In this study, cfDNA methylation exhibited better effectiveness than ctDNA mutation and serum protein markers in the early detection of gastric cancer. Based on cfDNA methylation, ctDNA mutation might not further provide value for the detection of gastric cancer. Our study highlights the potential clinical utility of the methylation-based early detection model for gastric cancer. A further expanded validation study is ongoing. Clinical trial information: NCT05224596.