Background: In coronavirus disease 2019 (COVID-19), finding sensitive biomarkers is critical for detecting severe cases early and intervening effectively. Objectives: To compare and evaluate the prognostic value of C-reactive protein (CRP), interleukin-6 (IL-6) and their derived immune-inflammatory indices (CRP/albumin (CRP/alb), lymphocyte/CRP (L/CRP), and lymphocyte/IL-6 (L/IL-6)) in COVID-19 patients. Methods: On admission, 85 confirmed COVID-19 patients’ measured and collected laboratory data were obtained and compared. Results: Levels of CRP, IL-6 and CRP/alb were significantly higher (P=0.001) in severe patients and in non-survivors, but L/CRP and L/IL-6 were significantly lower (P=0.001). The best predictive performance for COVID-19 severity was observed at 1.65 for CRP/alb and 260.86 for L/CRP with 84.7% diagnostic accuracy for both. The best diagnostic accuracy for COVID-19 in-hospital mortality was 87.1% by IL-6 at 120 pg/ml and 85.9% by L/IL-6 at 5.40. The performance of the combined prediction was better than the single prediction by one biomarker. IL-6 was an independent risk factor associated with severe disease development (odds ratio (OR): 1.033; 95% confidence interval (CI): 1.002-1.066). Conclusions: Pretreatment values of CRP, IL-6 and their derived indices could be included in the diagnostic work-up of COVID-19 to stratify disease severity and predict outcomes.