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Background: Moral distress is characterized by biopsychosocial, cognitive, and behavioral effects experienced by clinicians when their values are compromised by internal or external constraints, which results in the inability to give the desired care to patients. Objective: To assess predictors of moral distress among nurses working in Jimma University Medical Center, South West Ethiopia. Methods: An institution-based cross-sectional study design was used. A simple random sampling technique was applied to select a total of 248 study participants. Data were collected using a structured self-administered questionnaire, which contains socio-demographic characteristics, Moral Distress Scale-Revised, personal factors, and organizational factors. The data were entered into Epi-data version 3.1 and analyzed by SPSS software version 20. Descriptive statistics, bivariate analysis, and multivariable logistic regression analysis were performed. Finally, P-value <0.05 was used to declare and include variables with statistically significant in predicting the outcome variable. Results: More than two-thirds of the study participants 170 (68.5％) were females. The mean age of the respondents is 29 years. Among the study par ticipants, 174 (70.16％) nurses had experienced a high level of moral distress. Sex, working hours, professional commitment, autonomy, and working environment were statistically significant predictors of moral distress. Conclusions: More than two-thirds of the nurses were experiencing a high level of moral distress. This will affect the nursing service quality, nurses, the nursing profession, and the organization as a whole. This finding is critical for the study since the problem is happening in the presence of low nurse to patient ratio and low nursing care quality. Sex, working hours per week, professional commitment, autonomy, and working environment were identified as predictors of moral distress.