Patients suffering from ischemic stroke carry an enhanced risk of developing secondary epilepsy. We sought to clarify whether thrombolytic treatment with recombinant tissue plasminogen activator (t-PA) is independently associated with post-stroke epilepsy (PSE). In this observational study, data from 302 stroke patients treated at a single academic neurological department were analyzed retrospectively. Median follow-up was 42 months (maximum 80). Variables included presence of comorbidity, stroke severity, neurological presentation, complications, infarct characteristics, and treatment with t-PA. After univariate analyses, a multivariate analysis was performed to create a model of factors that were significantly associated with PSE, including treatment with t-PA. 13.9 % of patients developed PSE during follow-up. Multivariate analysis identified 5 independent factors for PSE: low Barthel Index at discharge; hemianopia; infection acquired during the hospital stay; involvement of the temporal lobe; involvement of the perirolandic cortex. While the incidence of PSE was higher in patients treated with t-PA (20.6 vs. 10.7 %, univariate analysis; p = 0.020), the effect was lost after adjusting for several factors associated with t-PA treatment [odds ratio for PSE after treatment with t-PA 1.3 (95 % CI 0.6–2.9), p = 0.489]. This study failed to identify treatment with t-PA as an independent risk factor for PSE.