<b>Background:</b> Sardinia, insular Italy, represents a particular epidemiological setting to investigate polyfactorial diseases, by virtue of its phylogeny and geographic isolation over time and of a well-established network of health operators and information systems. We present the first prevalence study of epilepsy conducted on a large Sardinian population by means of multiple source ascertainment. <br><b>Methods:</b> Cases were ascertained in the province of Sassari (population of 333,576) for the period between January 1, 2000 and December 31, 2008 based on records from (a) the District Center for Epilepsy, (b) the District Health Information System Unit, and (c) the neurologists practicing within the National Health System.</br> <b>Results:</b> The total crude prevalence of active epilepsy on December 31, 2007 was 6.62 per 1,000 (95% CI 5.3–7.9), 6.51 in men (95% CI 5.4–7.6), and 6.73 in women (95% CI 5.7–7.7). The highest prevalence (8.78 per 1,000) was estimated in the elderly (≥65 years). 50.5% were symptomatic epilepsies. Of these, over 50% were secondary to cerebrovascular disorders in the elderly. <br><b>Conclusions:</b> The epidemiological behavior of prevalence of active epilepsy in Sardinia appears to be in line with that of other developed countries, despite the role that population-specific genetic and environmental factors exert in modulating the risk for other neurological diseases. The action of (exogenous) factors commonly distributed in western populations, also influencing, at least partially, the epidemiological patterns of epilepsy in Sardinians, should not be ruled out.</br
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