Preventive therapy is aimed at reducing migraine frequency, but should also improve the much deteriorated quality of life of the migraneur. We aimed to evaluate the impact of preventive therapy with two widely employed drugs (topiramate and nadolol) on the quality of life of migraine patients. A population of consecutive migraineurs aged ≥16 years, with frequent migraines, was selected prospectively for evaluation at baseline and after 16 weeks of therapy with nadolol or topiramate (40 mg and 100 mg daily, respectively) by generic and specific quality of life questionnaires (SF-36 and MSQOL) and by an anxiety and depression scale (HADS). Preventive therapy resulted in a statistically significant improvement in physical domains of the SF-36, whereas mental domains remained almost unchanged. Despite this improvement, all domains remained below the population norms. The HADS revealed a moderate depressive state at baseline that did not change with therapy. The MSQOL global score also revealed statistically significant improvement. Both drugs were similarly effective, although topiramate was superior on the role physical domain compared with nadolol. Preventive therapy with nadolol and topiramate significantly improves the quality of life of migraineurs, although additional efforts are needed to place them in a nearer-to-normal situation compared with the general population.