Purpose:More than 20% of epilepsy patients have refractory seizures. Treatment options for these patients include continued polytherapy with/without novel antiepileptic drugs (AEDs), epilepsy surgery (ES), or vagus nerve stimulation (VNS). The purpose of this study was prospectively to compare epilepsy-related direct medical costs (ERDMCs) incurred by these different treatment modalities. Methods: Eighty-four patients underwent a complete presurgical evaluation protocol at our institution. As a result, 24 (29%) patients were treated with continued AED polytherapy only, 35 (40%) underwent ES; and 25 (30%) had VNS. In each patient, annual costs in the 2 years preceding the therapeutic decision (ERDMC-pre) and during the follow-up afterward (ERDMC-post) were prospectively calculated. Furthermore, frequency of complex partial seizures with/without secondary generalization (CPS +/- SG), dosage and number of AEDs, number of hospital admission days, clinic visits, and laboratory tests before and after the therapeutic decision also were prospectively assessed. ERDMC-pre and ERDMC-post were compared in and among the three treatment groups. Results: In patients conservatively treated with AEDs, mean frequency of CPSs decreased from 12 per month to nine per month, whereas mean ERDMCs decreased from $2,525 U.S. to $2,421 U.S. In surgical patients, rnean seizure frequency decreased from six to fewer than one per month; mean ERDMCs per year decreased from $1,465 U.S. preoperatively to $1,186 U.S. postoperatively. In the VNS group, mean seizure frequency decreased from 21 per month to seven per month. ERDMCs in this subgroup decreased from $4,826 U.S. to $2,496 U.S. Mean seizure frequency changes were significant when conservatively treated patients were compared with surgically treated and VNS patient groups (X-2 test, p<0.001 and p = 0.0019, respectively), ERDMC changes in conservatively treated patients also were statistically significant when compared with surgically treated and VNS patients (X2 test, p = 0.0007 and p = 0.0036, respectively). No statistically significant differences were found in ERDMC changes between the surgical and VNS groups (X2 test. p = 0.387). Conclusions: Ongoing daily treatment of patients who underwent resective surgery costs significantly less than conservative treatment. For patients in whom resective surgery is not an option, ERDMC show a significant decrease in VNS-treated patients compared with conservatively treated patients.