Background: Current guidelines do not recommend primary prophylactic anti-epileptic drug (AED) therapy for patients with brain metastases (BM). Yet, subgroups of patients at high seizure risk might still benefit from prophylaxis. Methods: We identified 799 patients diagnosed with BM by retrospective screening of our electronic chart system. Candidate risk factors for the development of epilepsy were tested by univariate and multivariate Cox regression models. Results: Epilepsy was diagnosed in 226 of 799 patients (28%). Risk factors for epilepsy in non-operated patients were single BM (P = 0.002, hazard ratio [HR] 3.2, 95% CI: 1.5-6.6) and detection of tumoral hemorrhage (P = 0.008, HR 2.5, 95% CI: 1.3-4.9). Preoperative seizures occurred predominantly in patients with supratentorial BM (P = 0.003, HR 20.78, 95% CI: 2.8-153.4) and lung cancer (P = 0.022; HR 2.0, 95% CI: 1.1-3.6). Postoperative seizures were associated with supratentorial localization (P = 0.017, HR 5.8, 95% CI: 1.4-24.3), incomplete resection (P = 0.005, HR 4.6, 95% CI: 1.6-13.1), and by trend for multiple brain surgeries (P = 0.095, HR 1.9, 95% CI: 0.9-4.0). These risk factors were integrated into a predictive score model for postoperative epilepsy (score sum 0-8). A gradual increase of seizure rates along with higher sum score was confirmed post hoc (score 0 = no seizures; score 8 = 48% seizures). Receiver operating characteristic analysis supported diagnostic accuracy (P = 0.00001, area under the curve = 0.75). Conclusions: Here we have defined risk profiles for the development of BM-related epilepsy and derived a score which might help to estimate the risk of postoperative seizures and identify individuals at risk who might benefit from primary prophylactic AED therapy.