Abstract Background: High performance work systems (HPWS) considered one of the most vital concerns in human resources management that enhance safety climate and improve nurses' thriving at work. Aim: The study aimed to investigate high performance work systems and its relation to safety climate and nurses' thriving at work at Main Mansoura University Hospital. Design: Was used a descriptive correlational design to achieve the aim of the study. Setting: The study was carried out on 131 staff nurses employed at all inpatient units at Main Mansoura University Hospital. Tools: Data were gathered through three tools namely, HPWS Scale, safety climate scale and thriving at work scale. Results: There was a statistically significant positive correlation between HPWS and safety climate. Dimensions of HPWS have positive correlations with dimensions of safety climate except employment security. In addition to that, a statistically significant positive correlation was found between HPWS and nurses' thriving at work. Also, dimensions of HPWS have positive correlations with dimensions of nurses thriving at work. Conclusion: HPWS have a significant impact on increasing safety climate and nurses' thriving at work. Recommendations: Implementing HPWS by hospital administrators through enhancing training and development, compensation, transformational leadership, employment security, teamwork and participation in decision-making that increase safety climate and thriving at work.