Background and aims During the COVID-19 vaccination program in India, the healthcare workers were given the first priority. There are concerns regarding the occurrence of breakthrough infections after vaccination. We aimed to investigate the effictiveness of COVID-19 vaccines in preventing and reducing the severity of post-vaccination infections. Methods This retrospective test-negative case-control study examined 28342 vaccinated healthcare workers for symptomatic SARS-CoV-2 infections between January 16 to June 15, 2021. They worked at 43 Apollo Group hospitals in 24 Indian cities. These cohorts received either ChAdOx nCOV-19 (Recombinant) or the whole virion inactivated Vero cell vaccines. Various demographic, vaccination related and clinical parameters were evaluated. Results Symptomatic symptomatic post-vaccination infections occurred in a small number of vaccinated cohorts (5.07%, p < 0.001), and these were predominantly mild and did not result in hospitalization (p < 0.0001), or death. Both vaccines provided similar protection, with symptomatic infections in 5.11% and 4.58%, following ChAdOx nCOV-19 (Recombinant) and the whole virion inactivated Vero cell vaccines, respectively (p < 0.001). Nursing and Clinical staff and cohorts >50 years contracted more infections (p < 0.001). Two-dose vaccination has significantly lower odds of developing symptomatic infection (0.83, 95%CI – 0.72 to 0.97). Maximum infections occurred during the peak of the second COVID-19 wave from mid-April to May 2021 (p < 0.001). No significant difference existed in the infection between sex, vaccine type, and the number of vaccine doses received (p ≥ 0.05). Conclusion Symptomatic infections occurred in a small percentage of healthcare workers after COVID vaccination. Vaccination protected them from not only infection but also severe disease.