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Background: Healthcare workers (HCWs) are at high risk of experiencing work-related stress, burnout syndrome, and depression, especially during infectious disease outbreaks like COVID-19. Contributing factors include increased workload, lack of personal protective equipment, and inadequate support from the healthcare administration. Longitudinal studies have shown that the mental health status of HCWs has deteriorated over time. Social support and compassion satisfaction (CS) are protective factors that can mitigate adverse mental health effects. The present longitudinal study examined the mental health status of HCWs during the COVID-19 outbreak and aimed to identify potential predictors and protective factors. Methods: The study comprised 386 healthcare workers in Hungary and was conducted in two waves (T1 and T2) from January 2021 to January 2022. Participants completed an online survey including the Professional Quality of Life Scale, Maslach Burnout Inventory, demographic and work-related background factors. Statistical analyses included descriptive statistics, and a cross-lagged panel model (CLPM). Results: Frontline HCWs had higher levels of secondary traumatic stress (STS) and emotional exhaustion (EE) than non-frontline healthcare workers. Both groups experienced significant increases in these measures between T1 and T2. The CLPM indicated that EE had a significant lagged effect on STS among frontline workers, while STS had a significant lagged effect on EE among non-frontline workers. CS had a significant protective effect on both STS and EE in both groups. Conclusions: The findings suggest that CS protects EE and STS, particularly among frontline HCWs. The study also showed that different causative relationships exist between these factors among frontline and non-frontline HCWs, which underlines the possible cyclical relationship between the two depending on the circumstances. The results provide insights into the protective role of positive work experiences and the importance of considering the needs of both frontline and non-frontline HCWs in preventive intervention programs. [ABSTRACT FROM AUTHOR]