The paper examines the role of macro and microeconomic determinants in bank profitability in EU-27. To identify how defined variables can affect profitability, the regression model with the multicollinearity condition, the multicollinearity below the defined value, was constructed. Data were collected based on 3257 bank balance sheet statements and the World Bank and Orbis Focus Bank Database. Based on the literature review, we have stated that the bank sector profitability is measured by Net Interest Margin (NIM), Return on Average Assets (ROAA) and Return on Average Equity (ROAE) as dependent variables. The statistical model showed no acceptable solution for the return on average equity. Four allowable solutions were found for the profitability of average assets and six solutions for the net interest margin. Finally, the results indicate the clear effect of rising inflation on the increase in banks' interest rates, thus higher interest margins. A healthy economy, also characterized by a growing GDP rate, also positively affects the interest margin.