The COVID-19 epidemic showed inter-regional differences in Italy. We used an ecological study design and publicly available data to compare the basic reproduction number (R0), the doubling time of the infection (DT) and the COVID-19 cumulative incidence (CI), death rate, case fatality rate (CFR) and time lag to slow down up to a 50-days doubling time in the first and the second 2020 epidemic waves (δDT50) by region. We also explored socio-economic, environmental and lifestyle variables with multiple regression analysis. COVID-19 CI and CFR changed in opposite directions in the second vs. the first wave: the CI increased sixfold with no evidence of a relationship with the testing rate; the CFR decreased in the regions where it was initially higher but increased where it was lower. The R0 did not change; the initially mildly affected regions, but not those where the first wave had most severely hit, showed a greater δDT50 amplitude. Vehicular traffic, average temperature, population density, average income, education and household size showed a correlation with COVID-19 outcomes. The deadly experience in the first epidemic wave and the varying preparedness of the local health systems might have contributed to the inter-regional differences in the second COVID-19 epidemic wave.