Background: No prophylactic treatment is available for individuals at high risk of developing COVID-19. This study, which was conducted between December 25, 2020 and January 25, 2021, is one of the first clinical studies to evaluate the efficacy of Anatolian propolis supplement against COVID-19. The aim was to obtain evidence on the prophylactic use of Anatolian propolis in individuals at high risk of developing COVID-19. Methods: This volunteer-based study was conducted in two centers. Study involved 209 healthcare professionals (physicians, nurses, medical secretaries) from Emergency Medicine Department of Medical Faculty of Ataturk University and Emergency Medicine Department of Rize Recep Tayyip Erdogan University. 209 participants meeting the study criteria were divided into two groups as experimental group and control group. The experimental group received 20 drops of BEE'O UP 30% Propolis Drops twice a day during a follow-up period of 1 month. The control group received no supplement but was followed up. Findings: The participants showing symptoms during the study and all the participants at the end the study were subjected to PCR testing. The evaluation of the results of PCR testing at the end of the study has shown that 14 participants from the control group and only 2 participants from the experimental group, who received Anatolian propolis supplement, were reported as positive cases. Interpretation: It has been found that a statistically significant protection was induced against COVID-19 infection in 98% of the experimental group, who received Anatolian propolis, compared to the control group.