© 2021 Elsevier Inc.Thiol-disulphide homeostasis (TDH) is a new parameter indicating oxidative stress that plays a role in the pathogenesis of various clinical disorders. Our study planned to investigate TDH in COVID-19 patients. Age and gender-matched healthy subjects (n = 70) and COVID-19 patients (n = 144) were included in the study. In addition to the routine laboratory parameters of the groups, their native thiol (NT), total thiol (TT) and disulphide levels were measured. Primarily, we compared COVID-19 patients to the healthy control group for inflammatory parameters, NT, TT and disulphide levels. Then, COVID-19 patients were divided into two groups according to the severity of the disease as mild to moderate and severe COVID-19, and the three groups were compared with each other. Predictive value of thiol parameters in the diagnosis of COVID-19 and in the determining its severity, and its correlation with presence and duration of symptoms were investigated. Severe COVID-19 patients had lower NT and TT levels compared with healthy controls and mild to moderate patients (P < 0.001 for both). The results of ROC analysis show that the greatest AUC was IL-6 and NT (AUC = 0.97, AUC = 0.96, respectively) between control and COVID-19 patients, while it was CRP and NT (AUC = 0.85, AUC = 0.83) between mild to moderate and severe patients. A negative correlation was found between duration of symptoms of dyspnoea, cough, fever, and sore throat and NT (r = −0.45, P = 0.017, r = −0.418, P < 0.001, r = −0.131, P = 0.084, r = −0.452, P = 0.040, respectively). NT and TT levels have a strong predictive value in the diagnosis of COVID-19 and in determining disease severity. Our results support that changing TDH parameters appears to have an important role in disease pathogenesis and it can be used in clinical management of patients.