Introduction: COVID-19 was declared a global pandemic in March 2020 by WHO. Until July 2022, there have been 555 million people suffering from this disease with a death toll of 6.35 million worldwide. Systemic inflammation triggered by a cytokine storm in a hypercoagulable state is the leading cause of COVID-19 patients’ mortality. CRP and D-dimer are biomarkers that can clearly illustrate pathogenesis. This research aims to compare C-reactive protein (CRP) and D-dimer as a better predictor of mortality in COVID-19 patients. Methods: It is an analytical observational research supported by a retrospective cohort design. The research subjects were COVID-19 patients treated in the isolation room of Dr. Hasan Sadikin General Hospital, Bandung, Indonesia, between August 2020 and August 2021. CRP and D-dimer was taken during pneumonia phase and then was compared on the next steps using univariate, bivariate and prognostic statistical tests. The quality of the prognostic value was examined using the Receiver Operating Characteristic (ROC) curve to set the Area Under Curve (AUC) and discrimination value. Results: There were 195 subjects confirmed with COVID-19. CRP value was significant in mortality with a cut-off of 230.1 mg/dl (RR 1.561, 95% CI 1.117-2.182, p=0.05). D-dimer value was significant on mortality with a cut off of 1,810 ng/ml (RR 21,613, 95% CI 8,266-56,508, p= 0.0001). Prognostic test results showed the discrimination value for D-dimer set by the AUC was 96.8% (strong), while the CRP discrimination value was 65.7% (weak). Conclusion: It can be concluded that as a predictor of mortality in COVID-19 patients, D-dimer value has a better discriminatory value than CRP value.