This study aims to analyze the effect of Debt to Equity Ratio (DER) and Firm Size on Profitability proxy with Return on Asset (ROA) in Manufacturing company on the Indonesian Stock Exchange 2017-2019. The sample population in this study contains Manufacturing companies listed on the Indonesia Stock Exchange The number of companies used in this study were 127 company samples. The research data is quantitative data obtained from the quarterly financial report of Manufacture Companies. Data analysis using simple linear analysis with 5% significance level which aims to obtain how the overall influence of the relationship between Debt to Equity Ratio (DER), Firm Size variable and Return on Asset (ROA). The results showed that the variable Debt to Equity Ratio (DER) has a negative and significant effect on Return on Asset (ROA) with a value t greater than 0.005 and Firm Size has a negative and significant effect on Return on Asset (ROA) with a value t greater than 0.005. High DER ratio can give a picture of the negative effect on profitability and High Firm Size ratio can give a picture of the negative effect on profitability of Manufacture Company.