The Mediterranean rivals meet on Sunday in Kiev's Olympic Stadium, three weeks after they drew 1-1 in their opening match of the tournament's group stage.
As the defending champion and World Cup holder, Spain is bidding to win a third straight major title and to cement its place as one of the greatest national sides of all time.
It would also match Germany's record of winning three European Championship titles.
Only the unpredictable Mario Balotelli and a surprising Italy team—orchestrated by Andrea Pirlo—stand between Spain and what many see as its destiny.