Abstract This study explored the relationship between the concentrations of homoarginine and arginine and between homoarginine concentration and laboratory parameters in coronavirus disease 2019 (COVID-19) patients with different severity to demonstrate the role of homoarginine in the progress of COVID-19. The laboratory-confirmed COVID-19 patients were included from Peking University Third Hospital during December 2022 to January 2023. Serum, urine, and stool samples were collected from the patients and detected by liquid chromatography-mass spectrometry. Totally 46 patients were recruited, including 18 in the mild group, 19 in the severe group, and 9 fatal. The concentration of homoarginine was positively correlated with the concentration of arginine in serum (r = 0.50), urine (r = 0.55), and stool samples (r = 0.39), respectively (all P < 0.001). The serum concentration and urine concentration of homoarginine were lower in severe patients than in mild patients (both P < 0.05). 13 indicators reflecting immunity and coagulation, including but not limited to T cell, white blood cell, natural killer cell, interleukin 6 (IL-6), and IL-8, had statistically significant correlations with both disease severity and the homoarginine concentration. Patients with hypertension were significantly associated with the decreased serum homoarginine (odds ratio 10.905, 95% confidence interval 1.454 − 137.144). Our results suggest that the homoarginine plays a role in the progress of COVID-19, which may be achieved by influencing arginine metabolism.