Background: COVID-19 has caused a considerable number of hospital admissions in China since December 2019. Many COVID-19 patients experience signs of acute respiratory distress syndrome, and some are even in danger of dying. Objective: to measure the serum levels of D-dimer, Neutrophil-Lymphocyte count ratio (NLR), and neopterin in patients hospitalized with severe COVID-19 in Baghdad, Iraq. And to determine the cut-off values (critical values) of these markers for the distinction between the severe patients diagnosed with COVID‐19 and the controls. Materials and methods: In this case-control study, we collect blood from 89 subjects, 45 were severe patients hospitalized in many Baghdad medical centers who were diagnosed with COVID-19 infection, and 44 were apparently healthy subjects as a control. The time of collection is from September 15 th to December 31 th, 2021. The optimal cut-off points (critical values) and prognostic relevance of D-dimer, Neutrophil-Lymphocyte count ratio (NLR), and neopterin were investigated using (ROC) curves analysis. Results: In severe patients hospitalized with COVID-19 the levels of D-dimer, NLR, and neopterin were statistically significantly higher than in control participants (P< 0.005). The D-dimer, NLR, and neopterin tests have areas under the receiver operating characteristic (ROC) curves of 0.920, 0.90, and 0.74 respectively, and their critical values for the differentiation between the severe patients and control were 0.22 μg/ml, 2.56, and 3.02 nmol/L. Conclusions: D-dimer, NLR, and neopterin levels in sever COVID-19 patients were higher than control, with values of greater than 0.22μg/ml, 2.56 and 3.02nmol/L respectively was linked to a severe COVID-19infection with good sensitivity and selectivity.