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This paper demonstrates, using a panel data model, that mainly firm-specific (microeconomic) versus macroeconomic variables affect the long-run profitability of a group of banks in Mexico in the pre- and COVID-19 periods. Interbank deposit, deposit rate, bank size, size of non-performing loan portfolio, delinquency, operating expenses, traditional deposit, salary, unemployment, and interest rate have statistical influence on bank profitability, but this relationship changes in the COVID-19 period. These results can be useful in the decisions of the different areas of banks, as well as for the design of public policies aimed at maintaining the stability of the banking system. [ABSTRACT FROM AUTHOR]