Background: The first case of COVID-19 was reported in our country on November 11, 2020. As of 2023, a total of 869,385 cases and 2,128 deaths have been recorded nationwide. The World Health Organization (WHO) has recommended that countries use 15 vaccines from 11 manufacturers listed for emergency use. The WHO has advised low-income member states to prioritize vaccinating healthcare workers and other high-risk populations vulnerable to severe illness and death from COVID-19. The main goal of the coronavirus vaccination program is to prevent infection, complications, and death among priority target groups, such as healthcare workers and other populations at high risk of severe illness. The effectiveness of the vaccination is measured by its ability to reduce the risk of illness, hospitalization, and death from COVID-19-related complications among vaccinated individuals. While extensive research is being conducted globally to develop, evaluate, and assess the effectiveness and outcomes of COVID-19 vaccines, there has been limited research focused on these outcomes within our country. This gap highlights the need for and serves as the basis of the present study. Аim: To assess the risk of infection, hospitalization, and associated risk factors among healthcare workers vaccinated against COVID-19, and to examine the factors that influence these risks. Materials and Methods: A This follow-up study was conducted over an 80-week period—at weeks 12, 24, and 48—from February 23, 2021, to December 31, 2022. The study involved healthcare workers from Ulaanbaatar city and the aimags of Bayankhongor, Orkhon, Bulgan, Dundgovi, Darkhan-Uul, and Dornod. The study was conducted over a period of 1.5 years (80 weeks) following the administration of the first two doses of the COVID-19 vaccine. Data were collected from participants at three time points: before vaccination, after the second dose, and after each booster dose. A structured questionnaire comprising 7 sections and 49 questions was used for data collection, and the results were analyzed using SPSS version 26.0. Results: Of the total respondents, 574 (60%) worked in direct contact with infected individuals in the 'red zone,' while 370 (40%) worked in the 'yellow zone.' Additionally, 250 participants (27.1%) were healthcare workers from Ulaanbaatar city, and 674 (72.9%) were from rural areas. In our observational study, the risk of new infections among healthcare workers increased over time, rising from 38.4% at week 24 to 59.6% by week 80. Hospitalizations also increased during the follow-up period: 24 cases (2.6%) were recorded at week 12, 160 (17.3%) at week 24, 202 (21.9%) at week 48, and 204 (22.1%) by week 80. Among frontline workers in rural areas, those in Bayankhongor and Orkhon aimags exhibited a lower risk of infection compared to their counterparts in other aimags. Conclusion In our follow up study, an increase in the duration since primary immunization was associated with a higher risk of new infection among workers, rising from 38.4% at 24 weeks to 59.6% at 80 weeks post-vaccination. Administration of additional (booster) immunizations was associated with a reduced risk of subsequent infection. COVID-19 vaccination was associated with a reduced risk of complications necessitating hospitalization. Employment in rural settings and designated red zones was identified as a risk factor for incident infections, hospitalizations, and reinfections.