OBJECTIVES: To estimate expected clinical and economic consequences of induced changes in body weight associated with migraine headache prophylaxis with topiramate versus amitriptyline. METHODS: Lifetime incidence and costs of cardiovascular disease (CVD) were estimated for patients receiving topiramate or amitriptyline as migraine headache prophylaxis. Projections were based on a model of the clinical and economic consequences of overweight and obesity, and data from a recent six-month controlled clinical trial of these agents, which demonstrated that they were equally effective in preventing migraines. Analyses were undertaken for a hypothetical cohort of 1000 women, aged 35 to 44 years at therapy initiation, with pre-treatment body mass index (BMI) of 28. Topiramate patients were assumed to experience a 1.26 unit decrease in BMI at six months, based on clinical trial data; and amitriptyline patients were assumed to experience an increase of 1.51; changes were assumed to persist over a lifetime. Model outcomes included expected lifetime cumulative incidence of coronary heart disease (CHD) and stroke, and life expectancy. Expected lifetime costs were calculated based on estimated event risk and associated medical-care costs, using a third-party payer perspective. Costs were discounted at 3% annually. RESULTS: As a result of changes in BMI, the estimated prevalence of hypertension, hypercholesterolemia, and diabetes was higher for amitriptyline versus topiramate at all future ages. Amitriptyline patients were also estimated to develop an additional 18 cases of CHD (per 1000 patients) compared to those receiving topiramate. Life expectancy was 0.4 years longer for topiramate patients, and their lifetime cumulative direct costs of CVD and metabolic disease were about $3500 lower than those for amitriptyline. CONCLUSION: Migraine headache prophylaxis with topiramate rather than amitriptyline may yield important clinical and economic benefits as a result of differences in induced changes in body weight.