Background: Invasive bacterial diseases (IBD) are a serious cause of hospitalization, sequelae and mortality. Albeit a low incidence, an increase in cases due to H. influenzae was registered in the past 4 years and, in the Tuscany region, an excess of cases due to N. meningitidis since 2015 is alarming. The purpose of this study is to deepen the knowledge of IBD epidemiology in Tuscany with particular attention to temporal trends. Methods: Tuscan residents hospitalized for IBD from January 1st 2000 to March 18th 2016 were selected from the regional hospital discharge database based on ICD-9-CM codes. Age-specific and standardized hospitalization rates were calculated together with case-fatality rates (CFRs). A time-trend analysis was performed; whereas, prognostic factors of death were investigated through univariable and multivariable analyses. Results: The average standardized hospitalization rates for invasive meningococcal diseases (IMD), invasive pneumococcal diseases and invasive diseases due to H. influenzae from 2000 to 2016 were 0.6, 1.8, and 0.2 per 100,000, respectively. The average CFRs were 10.5%, 14.5% and 11.5% respectively with higher values in the elderly. Older age was significantly associated with higher risk of death from all IBD. A significant reduction in hospitalization rates for IMD was observed after meningococcal C conjugate vaccine introduction. The Annual Percentage Change (APC) was -13.5 (95% confidence interval (CI) -22.3; -3.5) in 2005-2013 but has risen since that period. Furthermore, a significant increasing trend of invasive diseases due to H. influenzae was observed from 2005 onwards in children 1-4 years old (APC 13.3; 95% CI 0; 28.3). Conclusions: This study confirms changes in the epidemiology of invasive diseases due to H. influenzae and IMD. Furthermore, attention is called to the prevention of IBD in the elderly because of the age group's significantly higher rate of hospitalizations and deaths for all types of IBD.