Background: Pandemic fatigue is one of mental issues caused by the prolonged COVID-19 pandemic situation and is affected by individual and environmental factors. The aim of the study is to identify pandemic fatigue and its related risk factors among university employees. Methods: A cross-sectional was done among employees of Universitas Indonesia between October and December 2021. Demographics and history of COVID-19 were obtained electronically by using a Google Form. Study subjects invited to attend physical and laboratory assessment. Mental emotional stress was assessed using the selfreporting questionnaire 20 (SRQ-20). Pandemic fatigue was assessed using the Lockdown Fatigue Scale (LFS). Risks were expressed as adjusted odds ratio (ORadj) and 95% confidence interval (CI) in multivariate analyses. Results: 519 employees enrolled in this study, 65% were pandemic fatigue. The risk factors of pandemic fatigue were mental-emotional stress (ORadj 13.30; 95% CI 5.27-33.56; P < 0.001), alcohol consumption (ORadj 2.10; 95% CI 1.14-3.87; P = 0.017), living in yellow/orange/red zone of COVID-19 (ORadj 1.73; 95% CI 1.11-2.72; P = 0.016), and unmarried (ORadj 1.59; 95% CI 0.98-2.56; P = 0.060). Lower education was a protective factor (ORadj 0.59; 95% CI = 0.38-0.93; P = 0.022). Conclusions: The majority of the university employees reported pandemic fatigue during the second year of COVID-19 pandemic. The presence of mental-emotional stress is the strongest risk factor. As COVID-19 pandemic is still ongoing, mental health problem should be managed properly among employees. © (2024), (University of Occupational and Environmental Health). All Rights Reserved.