Spontaneous intracranial hypotension results from cerebrospinal fluid leakage. Currently, the treatment of choice for spontaneous intracranial hypotension is the epidural blood patch, which has a variable response rate and no clear outcome predictors. This study aimed to identify predictors for response rate of a first targeted epidural blood patch in patients with spontaneous intracranial hypotension. We reviewed cases of patients with spontaneous intracranial hypotension who received targeted epidural blood patch at our hospital between 1 January 2007 and 1 July 2014. The outcome measure was first epidural blood patch response. We analysed demographics, clinical manifestations, neuroimaging findings (non-contrast heavily T2-weighted magnetic resonance myelography and brain magnetic resonance imaging), and blood volume as potential outcome predictors. Significant predictors were tested and a decision tree was used to construct a predictive model. In total, 150 patients with spontaneous intracranial hypotension were included for final analyses. Their overall first targeted epidural blood patch response rate was 58.7%. Among patients with a greater injected blood volume (≥22.5 versus <22.5 ml), the response rate was higher (67.9% versus 47.0%, P = 0.01). In brain and spinal magnetic resonance imaging studies, significant predictors included anterior epidural cerebrospinal fluid collection length (<8 versus ≥8 segments; 72.5% versus 37.3%, odds ratio = 4.4, 95% confidence interval: 2.2–8.9, P < 0.001) and midbrain-pons angle (≥40° versus <40°; 71.3% versus 37.5%, odds ratio = 4.1, 95% confidence interval 2.1–8.3, P < 0.001). Decision tree analyses showed that patients with anterior epidural CSF collection involving <8 segments and an injected blood volume ≥22.5 ml had an 80.0% response rate. Patients with anterior epidural cerebrospinal fluid collection involving ≥8 segments and a midbrain-pons angle <40° had a 21.2% response rate. These three variables predicted first epidural blood patch response in 71.3% of patients. Brain and spinal neuroimaging findings and epidural blood patch blood volume can be used to predict targeted first epidural blood patch response in patients with spontaneous intracranial hypotension.