Simultaneous electroencephalography and functional magnetic resonance imaging (EEG/fMRI) have been proposed to contribute to the definition of the epileptic seizure onset zone. Following interictal epileptiform discharges, one usually assumes a canonical hemodynamic response function (HRF), which has been derived from fMRI studies in healthy subjects. However, recent findings suggest that the hemodynamic properties of the epileptic brain are likely to differ significantly from physiological responses. Here, we propose a simple and robust approach that provides HRFs, defined as a limited set of gamma functions, optimized so as to elicit strong activations after standard model-driven statistical analysis at the single subject level. The method is first validated on healthy subjects using experimental data acquired during motor, visual and memory encoding tasks. Second, interictal EEG/fMRI data measured in 10 patients suffering from epilepsy are analyzed. Results show dramatic changes of activation patterns, depending on whether physiological or pathological assumptions are made on the hemodynamics of the epileptic brain. Our study suggests that one cannot assume a priori that HRFs in epilepsy are similar to the canonical model. This may explain why a significant fraction of EEG/fMRI exams in epileptic patients are inconclusive after standard data processing. The heterogeneous perfusion in epileptic regions indicates that the properties of brain vasculature in epilepsy deserve careful attention.