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With the introduction of COVID-19 vaccines, many colleges and universities decided to mandate vaccination for all students and employees. The objective of this paper is to empirically investigate the effect of the mandate policy on Fall 2021 COVID-19 cases in institutions of higher education. We construct a unique dataset of a sample of 94 colleges and universities in the east and southeast regions of the United States, 41 of which required vaccination prior to Fall 2021. A difference-in-differences analysis is conducted, considering vaccine requirement as a policy implemented only in a sub-group of these institutions. We control for several factors, including state-level case per capita and student population. Our analysis shows that mandatory vaccination substantially decreased cases in institutions of higher education by 1,473 cases per 100,000 student population (95 CI: 132, 2813). The results suggest that a COVID-19 vaccine requirement is an effective policy in decreasing cases in such institutions, leading to a safer educational experience. [ABSTRACT FROM AUTHOR]