E-commerce can optimize the communications between producers, distributors, consumers, and even policy makers. However, due to many reasons, the application of e-commerce by small and medium-sized enterprises (SMEs) in developing economies is still limited. This study focuses on determining the determinants of the application of E-commerce model in SMEs in Ho Chi Minh City. Then, some policy implications are proposed to promote e-commerce model in SMEs in Ho Chi Minh City. Based on the survey of 302 SMEs in Ho Chi Minh City, the paper has employed statistical methods, assessing the reliability by Cronbach's Alpha scale, Exploratory Factor Analysis (EFA), correlation analysis as well as linear regression model (OLS) for analysis. The results show that the enterprise's readiness, awareness of benefits of e-commerce and supporting policies positively affect the application of E-commerce. E-commerce adoption barriers negatively affect E-commerce applications of SMEs in Ho Chi Minh City.