Neutrophil elastase (NE), myeloperoxidase‐DNA (MPO‐DNA), histone‐DNA, and (B) cell‐free dsDNA and total DNase activity in serum of 155 COVID‐19‐positive cases. Symptomatic ambulatory cases (n = 34) were recruited in screening centers and hospitalized patients (n = 122) in local hospitals (n = 43) and in medical departments (n = 65) and intensive care units (n = 13) of two regional university hospitals. The p‐values of NE concentrations between groups were as follows: healthy versus ambulatory <0.0001; healthy versus proximity hospital <0.0001; healthy versus medical department <0.0001; healthy versus intensive care <0.0001; ambulatory versus proximity hospital 0.7870; ambulatory versus medical department 0.0028; ambulatory versus intensive care <0.0001; proximity hospital versus medical department 0.0003; proximity hospital versus intensive care <0.0001; and medical department versus intensive care 0.0239. The p‐values of MPO concentrations between groups were healthy versus ambulatory <0.0001; healthy versus proximity hospital <0.0001; healthy versus medical department <0.0001; healthy versus intensive care <0.0001; ambulatory versus proximity hospital 0.1237; ambulatory versus medical department 0.8589; ambulatory versus intensive care 0.1276; proximity hospital versus medical department 0.1463; proximity hospital versus intensive care 0.5811; and medical department versus intensive care 0.1482. The p‐values of histone_DNA values between groups were healthy versus ambulatory <0.0001; healthy versus proximity hospital <0.0001; healthy versus medical department <0.0001; healthy versus intensive care <0.0001; ambulatory versus proximity hospital 0.0013; ambulatory versus medical department 0.0525; ambulatory versus intensive care <0.0001; proximity hospital versus medical department 0.2740; proximity hospital versus intensive care 0.0.0033; and medical department versus intensive care 0.0003. The thresholds (dotted lines) were evaluated in healthy controls recruited several months before the epidemy. The threshold of NE was estimated at 73 ng/ml and those of MPO‐DNA at 0.562 AU (450 nm absorbance units), histone‐DNA at 0.591 AU, total activity of DNase at 9.94 U/ml, and serum dsDNA at 95.60 ng/ml (C) NE, MPO‐DNA, and histone‐DNA according to the number of organs affected by COVID‐19. Data from (A), (B) and (C) were compared by the Mann‐Whitney test. The dashed lines represent the cutoffs defined by the mean +2 standard deviations for NE, MPO‐DNA, histone‐DNA, cell‐free DNA, and the mean—2 standard deviations for DNase activity