Background To develop and validate an easy-to-use scoring system to predict the response to the first epidural blood patching in patients with spontaneous intracranial hypotension. Methods This study recruited consecutive patients with spontaneous intracranial hypotension receiving epidural blood patching in a tertiary medical center, which were chronologically divided into a derivation cohort and a validation cohort. In the derivation cohort, factors associated with the first epidural blood patching response were identified by using multivariable logistic regression modeling. A scoring system was developed, and the cutoff score was determined by using the receiver operating characteristic curve. The findings were verified in an independent validation cohort. Results The study involved 280 patients in the derivation cohort and 78 patients in the validation cohort. The spontaneous intracranial hypotension-epidural blood patching score (range 0–5) included two clinical variables (sex and age) and two radiological variables (midbrain-pons angle and anterior epidural cerebrospinal fluid collections). A score of ≥3 was predictive of the first epidural blood patching response, which was consistent in the validation cohort. Overall, patients who scored ≥3 were more likely to respond to the first epidural blood patching (odds ratio = 10.3). Conclusion For patients with spontaneous intracranial hypotension-epidural blood patching score ≥3, it is prudent to attempt at least one targeted epidural blood patching before considering more invasive interventions.