Has partisan polarization reached the stage that it now affects Americans’ decisions whether or not to get vaccinated against a pervasive and deadly virus such as COVID-19? To date, the evidence has largely been hypothetical—collected before the vaccine was widely available—superficial, or contradictory. Using two original surveys conducted at two different time periods after vaccines became available, this study represents one of the first efforts to systematically analyze the role of party affiliation in predicting vaccine hesitancy. We find that even after controlling for a host of demographic and attitudinal variables, Republicans are significantly less likely—and Democrats more likely—to be vaccinated, to be willing to be vaccinated, and to recommend vaccination to a friend who asks for advice. In addition to these direct effects, we also uncover evidence that partisanship affects vaccine hesitancy indirectly through its influence on Americans’ concern over COVID, belief in vaccine conspiracy theories, and trust in government, science, and the medical profession. These findings support the idea that policymakers seeking to increase COVID vaccination rates may need to engage in specialized outreach not only to specific socio-economic communities, but also to specific partisan communities.