OBJECTIVES: Health economic evaluation on the relative value of lamotrigine (LTG) and levetiracetame (LEV) in the initial monotherapy of epilepsy METHODS: Paralleling an open label, prospective, randomised, multicenter trial including 409 epilepsy patients, a health economic evaluation of 81 participants aged ≥18 years was conducted. Data collection was done by the CRF of the clinical trial and in a series of three telephone interviews (baseline and two follow up calls, 3 and 6 months after baseline, respectively). The telephone interviews comprised sociodemographics, as well as instruments for the evaluation of health-related quality of life, depression and resource use). RESULTS:  Eighty-one epilepsy patients were included in the economic evaluation. Thirty-eight (46.9%) patients were female: 21 (53.8%) in the LTG arm and 17 (40.5%) in the LEV arm. The mean duration of the disease was 2.0±3.9 years (LTG) and 2.2±6.1 years (LEV). Over the survey period, there was no significant difference concerning the number of ambulatory consultations (LTG 28 vs. LEV 26) or stationary hospital care (LTG 33 vs. LEV 38), though there was a trend for more ambulatory hospital care in the LTG group (LTG 20 vs. LEV 10). No significant difference was found concerning the self-reported health status of the patients (mean EQ VAS at follow-up: LTG 75.2±18.1 vs. LEV 74.8±24.7) nor depression (mean BDI sumscore at follow-up: LTG 7.1±5.9 vs. LEV 5.9±7.5). CONCLUSIONS: No significant differences were detected between the two treatment arms concerning ambulatory or stationary resource use, self-reported health status or depression. Non-inferiority should be proven with an adequate trial design.