Background: Nursing is highly demanding and stressful profession. Job stress was found to be a stronger predictor of oxidative stress activity causing elevation of blood oxidative biomarkers. This work aimed to improve mental and psychological health of nurses through identification of prevalence of work stress among nurses at Zagazig university hospitals (ZUHs) and assess the association between work stress and blood oxidative biomarkers. Methods: A comparative cross-sectional study was conducted among 40 nurses and 40 administrative workers at ZUHs. Both two groups were subjected to a structured questionnaire about sociodemographic data and occupational history and two standardized questionnaires about job stress followed by laboratory investigations to measure blood oxidative biomarkers (Malonaldehyde MDA & Superoxide dismutase SOD). Results: This study showed that job stress and its level were significantly higher among nurses compared to their controls. this study indicated that prevalence of job stress in nurses at ZUHs was 85.0% compared to 22.5% in administrative controls where 65.0% and 20.0% of them had severe and moderate stress compared to 7.5% and 15.0% among controls.Furthermore, this study showed significantly high level of both blood oxidative biomarkers as both levels of MDA, [ Median (3.18) mol/ml] and SOD, [X±SD: 4.27± 0.40 U/ml] were significantly higher among nurses compared to their controls Conclusion: Job stress is realistic and widespread phenomena among nurses in ZUHs that have devastating consequences on nurse's health thus, effective preventive strategies should be designed and implemented.