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Introduction: Electronic personal health record (e-PHR) system enables individuals to access their health information and manage it themselves. It helps patient engagement management of health information that is accessed and shared with their healthcare providers using the platform. This improves individual healthcare through the exchange of health information between patients and healthcare providers. However, less is known about e-PHRs among healthcare professionals., Objective: Therefore, this study aimed to assess Health professionals' Knowledge and attitude and its associated factors toward e-PHR at the teaching hospital in northwest Ethiopia., Methods: An institution-based cross-sectional study design was used to determine healthcare professionals' knowledge and attitude and their associated factors toward e-PHR systems in teaching hospitals of Amhara regional state, Ethiopia, from 20 July to 20 August 2022. Pretested structured self-administered questionnaires were used to collect the data. Descriptive statistic was computed based on sociodemographic and other variables presented in the form of table graphs and texts. Bivariable and multivariable logistic analyses were performed with an adjusted odds ratio (AOR) and 95% CI to identify predictor variables., Result: Of the total study participants, 57% were males and nearly half of the respondents had a bachelor's degree. Out of 402 participants, ~65.7% [61-70%] and 55.5% [50-60%] had good knowledge and favorable attitude toward e-PHR systems, respectively. Having a social media account 4.3 [AOR = 4.3, 95% CI (2.3-7.9)], having a smartphone 4.4 [AOR = 4.4, 95% CI (2.2-8.6)], digital literacy 8.8 [(AOR = 8.8, 95% CI (4.6-15.9)], being male 2.7 [AOR = 2.7, 95% CI (1.4-5.0)], and perceived usefulness 4.5 [(AOR = 4.5, 95% CI (2.5-8.5)] were positively associated with knowledge toward e-PHR systems. Similarly, having a personal computer 1.9 [AOR = 1.9, 95% CI (1.1-3.5)], computer training 3.9 [AOR = 3.9, 95% CI (1.8-8.3)], computer skill 19.8 [AOR = 19.8, 95% CI (10.7-36.9)], and Internet access 6.0 [AOR = 6.0, 95% CI (3.0-12.0)] were predictors for attitude toward e-PHR systems., Conclusion: The findings from the study showed that healthcare professionals have good knowledge and a favorable attitude toward e-PHRs. Providing comprehensive basic computer training to improve healthcare professionals' expectation on the usefulness of e-PHR systems has a paramount contribution to the advancement of their knowledge and attitude toward successfully implementing e-PHRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wubante, Tegegne, Melaku, Mengiste, Fentahun, Zemene, Fikadie, Musie, Keleb, Bewoketu, Adem, Esubalew, Mihretie, Ferede and Walle.)