Background: Informed consent is the process of communication between a patient and health-care provider that results in the patient’s authorization/agreement to undergo a specific medical/surgical intervention. The practice of surgical informed consent among health care providers was considered as poor and the health care workers did not meet the minimum standards yet when they conducted informed consent with patients. Objective: This study was aimed to assess practice and factors associated with informed consent process for major surgical procedures among health-care workers In Wachemo University, Nigist Eleni Mohamed Memorial comprehensive specialized Hospital, Hosanna Southern Ethiopia.2022. Method: Institutional-based cross-sectional study was conducted among 422 health care workers from 9 August to 21, 2022. Each study units were selected based on the proportionally allocated sample size from each profession by simple random sampling method, self-administered pretested questionnaire was used to collect all necessary data. Then data was, entered into epi data version 3.1, exported to statistical package for social science version 25 for cleaning and analysis. The bivariate logistic regression model was used to explore factors associated with surgical informed consent practice, variables with p-value of <0.25 became candidates for final model (Multivariable logistic regression model). Then finally, odds ratio with 95% confidence interval and p-value of <0.005 was used to identify variables which were significantly associated with dependent variable. Results: A total of 422 sample size with 98.1% response rate, of which 223(53.9% (CI; 48.3-58.4) had good surgical informed consent practice. Being age between 31-35 years (AOR=2.392; 95% CI: 1.33-14.467), no language barrier in communication with patients (AOR=2.011; 95% CI: 1.848-8.511), availability of policy/regulation that support surgical informed consent process (AOR=3.201; 95% CI: 1.102-9.298), spending more time 21-30 minutes on consent process (AOR=5.006; 95% CI: 1.659-15.100), patients with history of previous surgery (AOR=3.141; 95% CI: (1.435-6.876), having good knowledge (AOR=3.931; 95% CI: 1.799-8.591) and favorable attitude (AOR=5.690; 95% CI: 2.729-11.862) were significantly and positively associated with good informed consent practice. Conclusion: The surgical informed consent practice is still inadequate for globally recommended standard among the health care workers at the comprehensive University Hospital. Recommendations: More emphasis and work up need for quality health service. Keywords: Health-care workers, Major surgeries, Surgical informed consent, Practice.