: As COVID-19 can be severe, early predictive markers of both severity and onset of secondary bacterial infections are needed. This study first examined changes over time in the levels of plasma neopterin (NP) and biopterins (BPs), among others, in patients with COVID-19 and then in those with secondary bacterial infection complications. : Fifty-two patients with COVID-19 admitted to two tertiary care centers were included. They were divided into a severe group (intubated + mechanical ventilation) ( = 10) and a moderate group (non-intubated + oxygen administration) ( = 42), and changes over time in plasma NP, plasma BPs, IFN-γ, lymphocyte count, CRP, and IL-6 were investigated. Four of the patients in the severe group ( = 10) developed secondary bacterial infections during treatment. Plasma NP and plasma BPs of patients with bacterial sepsis (no viral infection) ( = 25) were also examined. : The plasma NP, IL-6, CRP, and SOFA levels were significantly higher in the severe group, while the IFN-γ level and lymphocyte count were significantly lower. The higher plasma NP in the severe group persisted only up to 1 week after symptom onset. The plasma BPs were higher in complications of bacterial infection. : The timing of sample collection is important for assessing severity through plasma NP, while plasma BPs may be a useful diagnostic tool for identifying the development of secondary bacterial infection in patients with COVID-19. Further investigation is needed to clarify the mechanism by which NP and BPs, which are involved in the same biosynthetic pathway, are differentially activated depending on the type of pathogen.