The objective of this study is to identify factors that affect the profitability of rice farmers in the Mekong Delta, Vietnam. The study used stratified random sampling to collect data from 750 rice farmers in the Mekong Delta. Applying multivariate linear regression, the study has shown that reasonable investments in labor costs may enhance farmers’ profit. In contrast, the cost of seed, fertilizer, pesticide, machinery, and depreciated cost negatively affect the profitability of farmers. Besides, the study pointed out the positive impact of education and technical progress on the profitability of rice farmers in the Mekong Delta, Vietnam