Objective: During the COVID-19 pandemic, several vaccines that were efficacious in randomized controlled trials (RCTs) were authorized for mass vaccination. In developing countries, inactivated vaccines were widely administered. While inactivated vaccines have been deemed effective in reducing disease severity, for healthcare personnel (HCPs), effectiveness against COVID-19 infections is also essential to reduce the risk to vulnerable patients and ensure a stable healthcare workforce. In addition, there are limited studies examining effectiveness of inactivated vaccines against emerging SARS-CoV-2 variants in real-world settings. We aimed to estimate the effectiveness of inactivated vaccines (BBIBP-CorV and CoronaVac) against RT-PCR-confirmed COVID-19 infections among HCPs in the setting of emerging SARS-CoV-2 variants in Pakistan. Design, setting and participants: A retrospective matched test-negative case-control analysis of existing data of HCPs at a private healthcare system in Pakistan. Methods: HCPs tested between April 1 and September 30, 2021, were included. Each case was matched to two to six controls by the date of the RT-PCR test (± 7 days) to reduce bias. We compared demographics, reasons for testing, and vaccination status between cases and controls using chi-square for categorical variables and t-test for continuous-level data. The odds of getting a PCR-confirmed SARS-COV-2 infection were calculated using conditional logistic regression, after adjusting for age, gender, and work area. Vaccine effectiveness (VE) was calculated as percent VE using (1-OR)*100. Results: Inactivated vaccines were ineffective against COVID-19 infections ≥ 14 days after receiving the first dose [VE: 20% (95% CI: -10, 41; p=0.162)]. The vaccines showed modest effectiveness ≥ 14 days after the second dose against COVID-19 infections [VE: 33% (95% CI: 11, 50; p=0.006)], and symptomatic COVID-19 infections [VE: 36% (95% CI: 10, 54; p=0.009)]. Conclusions: Inactivated vaccines show modest effectiveness against COVID-19 infections in the setting of emerging VOCs. This builds a strong case for boosters and/or additional vaccination.