<p>Herd immunity for preventable childhood infectious diseases such as measles and mumps has come under threat in numerous countries, due to declining vaccination rates. This decline underscores the urgent need to understand the underlying mechanisms of vaccine skepticism. Institutional (dis)trust and belief in (vaccine) misinformation have been proposed as important factors, but their interconnectedness and potential mutual influence have remained elusive. Importantly, higher trust has been hypothesized to serve as a “buffer” against the adverse effects of misinformation belief. In this preregistered study (<i>N</i> = 1356, probability sample of Dutch households), we address these questions using validated, high-quality measures of vaccine attitudes, trust, and misinformation susceptibility. We find that specific trust in the government with respect to vaccinations is a much stronger predictor of vaccine skepticism than general trust in institutions. Moreover, susceptibility to misinformation is significantly associated with vaccine skepticism under all model specifications. Contrary to expectations, we find no evidence for the “buffer” hypothesis, suggesting that, while correlated, misinformation susceptibility and trust are distinctly related to vaccine skepticism.</p>