According to our research, the main difference lies in the milk frother. The EP2221/49 is equipped with a classic system that uses steam to froth milk manually according to your taste, whereas the EP2220/19 is equipped with a LatteGo milk system.The LatteGo milk system is an automatic frother that produces a specific texture that you don't have the option of dosing/adjusting according to your needs (but which is apparently easier to clean).