Background: Predictors of mortality in COVID-19 patients, which are essential factors in guiding patient management, are poorly understood. In Indonesia, several inflammatory markers have been utilized to evaluate the severity of COVID-19. This study aimed to determine the role of C-reactive protein (CRP), D-dimer, interleukin-6 (IL-6), and XCL1/lymphotactin levels in predicting 28-day mortality in patients with COVID-19.Methods: A prospective cohort study was conducted with COVID-19 patients admitted to the emergency department at Cipto Mangunkusumo Hospital and Medistra Hospital, Jakarta, Indonesia, from June 2020 to February 2021. The predictors of 28-day mortality in COVID-19 patients in this study included CRP, D-dimer, IL-6, and XCL1 levels at admission. Cox proportional hazard regression analysis was used to determine the independent predictors of 28-day mortality in the study population.Results: A total of 120 patients with COVID-19 were enrolled in the study; 21 (17.5%) died within 28 days after admission. According to our multivariate analysis, a CRP level (HR, 8.55; 95% CI, 3.310-22.088)≥ 110 mg/L and a D-dimer level (HR, 20.642; 95% CI, 6.909-61.667)≥ 4640 ng/mL were identified as independent predictors of 28-day mortality in COVID-19 patients.Conclusion: A C-reactive protein level≥ 110 mg/L and a D-dimer level≥ 4640 ng/mL can be used to predict 28-day mortality in COVID-19 patients.