Background and Objectives: The COVID-19 pandemic was mitigated by the rapid development and deployment of vaccines. While vaccines reduce infection severity, breakthrough infections (BTIs) still occur. The CDC defines BTI as a positive SARS-CoV-2 test ≥14 days post-vaccination. This study investigates the occurrence of COVID-19 BTIs at a tertiary care hospital in Puducherry, South India. Materials and Methods: This retrospective study analysed hospital tested qRT-PCR data of individuals from the ICMR portal (March 2021–March 2022). Demographic and vaccination details were extracted. Results: Among 8001 tested individuals, 1452 were vaccinated. The BTI rate decreased from 16.6% to 1.2% after the first dose and from 58% to 40% after the second one. Odds ratio indicated a 74% reduction in infection risk for vaccinated individuals compared to unvaccinated. Males had higher infection rates than females, regardless of vaccination status. Conclusion: Our study demonstrates a higher BTI rate after one vaccine dose compared to two doses. The BTI rate also increased four months post-vaccination, even with two doses, potentially due to waning immunity and the emergence of new variants. Therefore, continued adherence to preventive measures in conjunction with vaccination is crucial for minimizing COVID-19 transmission. © 2025 Elsevier B.V., All rights reserved.