We studied the impact of economic policy uncertainty on stock markets in the United States over the long period 1900–2014 using both linear and market switching models. Our findings show that an increase in policy uncertainty reduces significantly stock returns. However, the EPU-stock returns relationship is not linear and the effect of EPU on stock returns is stronger and persistent during extreme volatility periods. Our paper highlights the importance for the US authorities to maintain the transparency and stability of the implementation of economic policies to prevent the negative impacts of uncertainty on stock markets. A natural extension of our work would be to use alternative proxies for EPU. A good candidate is elections. This variable allows in particular to check whether stock market returns in months leading up to Presidential and/or mid-term elections are lower due to higher uncertainty.