The annual incidence of myasthenia gravis (MG) ranges from 3 to 30 per 1,000,000 people. Since the mid-1980s, an increasing incidence has been reported, mainly due to late-onset MG. Whether the increase was due to population aging, improved diagnosis and case collection, or a true excess of incidence cases is still under debate. We used a complete enumeration approach by reviewing all possible sources of case collection in the province of Ferrara, Italy, to estimate the MG incidence and its temporal trend over the study period (1985-2007). The mean annual age-adjusted incidence of MG was 18 per 1,000,000, without any significant temporal trend. The incidence rates in the period 1985-1990 were 14 both for early and late-onset MG. Thereafter, a significant increase in incidence of late-onset MG (p < 0.05), and a decrease in early onset MG were detected (p < 0.01). These findings were related to nonthymoma MG. The median age at onset of the disease steadily increased over time. A changing pattern of MG incidence with an increase in frequency of late-onset and a decrease of early onset MG was found in the last years, giving a significant shift to older age at onset of the disease. Unknown environmental factors may have driven this change in MG epidemiology.