Background Increased plasma nuclear and mitochondrial DNA levels may be connected to disease severity following spontaneous intra‐cerebral haemorrhage (ICH). This study tested the hypothesis that plasma nuclear and mitochondrial DNA levels are substantially increased in acute ICH and can predict treatment outcomes. Methods Serial plasma nuclear and mitochondrial DNA levels were examined in 60 consecutive patients admitted within 24 h after onset of spontaneous ICH and in 60 volunteer control subjects. Additional samples were obtained on days 4, 7, 10, and 14 after onset of ICH regardless of clinical deterioration. Results Only plasma nuclear DNA, not plasma mitochondrial DNA, levels in patients with spontaneous ICH significantly correlated with Glasgow Coma Scale (GCS) (r = −0.467, P = 0.001) and ICH volume (r = 0.515, P ≤ 0.001) on presentation. Plasma nuclear DNA levels increased significantly from day 1 to day 7 in patients with poor outcome. Higher plasma nuclear DNA levels (cut‐off value >18.7 ng/ml) on presentation were associated with poor outcomes in spontaneous ICH patients. Conclusion Plasma nuclear DNA levels reflect the severity of cerebral damage such that higher levels are associated with poorer outcome. Plasma nuclear DNA level can be considered a neuropathologic marker of acute spontaneous ICH.