Background: The rapid emergence of the novel corona virus disease 2019 (COVID-19) has resulted in millions of infected patients and deaths in worldwide. Studies conducted till today show that the outcome of COVID-19 varies based on individual characteristics. The purpose of this investigation was to identify the determinants of COVID-19 deaths in Amhara region. Objectives: The study aimed to identify the determinants of death among COVID-19 patients admitted in Amhara region covid-19 treatment centers, Ethiopia, 2021. Methods: Unmatched case control study design was conducted among 675 COVID-19 patients (135 case and 540 control by 1: 4 ratio) admitted in 8 COVID-19 treatment centers in Amhara region from march 1, 2020 to march 30, 2021. From study participants cases were all death in COVID-19 treatment centers and controls were selected using simple random sampling technique. Data were collected by using Epicollect5 software from 8 COVID-19 treatment centers and analyzed via STATA version 14. Mean, median and IQR were computed for cases and control groups and Variables that had (P- value <=0.25) in the bivariable logistic regression analysis were entered in multivariable logistic regression model. Finally Adjusted Odds ratio (AOR), 95% CIs for AOR, and P-values <0.05 were used to declare statistical significance and interpretation of results. Result: Analyses were done on 675 COVID-19 patients comprising 135 cases and 540 controls. Factors such as older age (AOR 1.14, 95% CI 1.11-1.17), male sex (AOR 3.63, 95% CI 1.74-7.55), rural residence (AOR 0.21, 95% CI 0.10-0.42), patients who had fever (AOR 3.65, 95% CI 1.72-7.75), Sign of respiratory distress (AOR 4.04, 95% CI 1.94-8.42), hypertension AOR (2.58, 95% CI 1.06-6.25) and diabetes mellitus (AOR5.3.39 % CI 1.33-8.64) were found to be independent determinants of Death. Conclusion and recommendation: Increment in age, male sex, urban residence, having fever and sign of respiratory distress at admission, comorbidity of diabetic mellitus and hypertension were found to be significant determinants of death among COVID-19 patients. Therefore interventions that target to the identified factors are recommended for concerned stakeholders to develop and implement Special care plan for a patient having comorbidity, age specific treatment guidelines, and careful evaluation of patients with fever and sign of respiratory distress with a more sensitive triage and doing researches using strong study designs. Key word: Amhara region, case-control, COVID-19, death, determinant