Conservatives in the United States have more negative attitudes toward COVID-19 vaccines and are less likely to be vaccinated than liberals. The present research tests whether political differences in knowledge underlie differences in vaccination. Participants in Study 1 completed a knowledge test about COVID-19 vaccines and indicated whether they had received a COVID-19 vaccine. Republicans had worse knowledge about COVID-19 vaccines than Democrats. Furthermore, political differences in vaccination were significantly mediated by knowledge. Study 2 found that exposure to facts about COVID-19 vaccines led to more favorable perceptions of vaccine effectiveness among Republicans, which in turn was associated with stronger vaccination intentions. These data suggest that knowledge about COVID-19 vaccines may help to explain political differences in vaccination.