Background: The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented threat to health care providers (HCPs) in Wuhan, China, especially for nurses who were frequently exposed to infected or suspected patients. Limited information was available about the psychological distress of nurses in fighting against the pandemic. Methods: In this cross-sectional, multi-center study, we enrolled 5,521 nurses from ten affiliated hospitals of Huazhong University of Science and Technology (HUST) (Wuhan, China) who participated in fighting against the pandemic. The data about demographic characteristics, work-related characteristics, and psychological distress were measured, and log-binomial regression analysis was performed to explore determinants of psychological distress. Findings: 5,221 of 9,110 contacted individuals completed the survey, with a participation rate of 57%. A considerable of nurses (4721 [86%]) reported psychological distress during the pandemic, with anxiety being the most common (4324 [83%]). Regression analysis showed nurse who were females (risk ratio [RR] 1·34, 95% CI 1·00-1·79; p=0·046), directly involved in care for infected or suspected patients (ie, care for mild/moderate patients: RR 1·28, 95% CI 1·05-1·58; p=0·02), and daily working overtime (RR 1·51, 95% CI 1·12-2·04; p=0·01) were at a higher risk for psychological distress. Nurses who worked outside designated hospitals (ie, mobile cabins: RR 0·56, 95% CI 0·41-0·78; p=0·001), with uniform requirement for job rotation (RR 0·29, 95% CI 0·21-0·41; p<0·0001) were at a lower risk for psychological distress. Interpretation: It is essential to formulate reasonable work shift rules and strengthen workforce reserves to alleviate psychological stress of frontline nurses during the pandemic. Funding Statement: No funding was received for this study. Declaration of Interests: Jie Li, Jing Mao, Quan Wang, Junyao Fan, Huimin Zhao, Yueting Liu, Xinxue Xi, and Linglin Kong, report no conflict of interest. Ethics Approval Statement: Approval was obtained from the respective Institutional Review Board before the initiation of this study.