〔Abstract〕 Objective To investigate the diagnostic efficacy and clinical value of GNB4 and Riplet gene methylation alone and in combination in the diagnosis of primary liver cancer.Methods A total of 313 patients were selected,including 78 patients with primary liver cancer, 41 patients with other digestive system tumors, 17 patients with non-digestive system tumors, 20 patients with postoperative liver cancer, and 157 patients with benign liver diseases.The levels of GNB4 and Ripletgene methylation in plasma were detected using quantitative methylation-specific PCR(qMSP).Serum alpha-fetoprotein(AFP) levels were measured by direct chemiluminescence.Results The sensitivity and specificity of AFP in diagnosis were 51.3% and 94.3%, respectively; the sensitivity and specificity of GNB4 gene methylation in diagnosis were 83.3% and 99.4%, respectively; the sensitivity and specificity of Riplet gene methylation in diagnosis were 73.1% and 99.4%, respectively.The sensitivity and specificity of GNB4andRipletgene methylation combined diagnosis were 92.3% and 98.7%, respectively; the sensitivity and specificity of AFP,GNB4andRipletgene methylation combined diagnosis were 92.3% and 98.7%, respectively;the sensitivity and specificity of combined diagnosis including age and gender were 93.6% and 97.5%, respectively.Conclusion The sensitivity and specificity of AFP in the diagnosis of primary liver cancer are limited, while the methylation levels of GNB4 and Ripletgenes are higher, and the sensitivity and specificity of their combined detection are higher than those of AFP.The sensitivity and specificity of AFP,GNB4 and Ripletgene methylation combined diagnosis are significantly higher than those of AFP,GNB4 and Ripletgene methylation alone.