Spain host Macedonia in Group C action in Valencia on Monday and the defending champions are expected to record a comfortable win, despite their horror showing at the World Cup and Thursday's friendly loss to France.
Macedonia are on a four-game winless run, having tasted defeat against Cameroon and China, while they were also held to a scoreless draw by minnows Qatar in May.
But Del Bosque - overseeing a new generation of players - is refusing to treat Bosko Gjurovski's men lightly as he looks set to name a strong side for the clash at the Estadio Ciudad de Valencia, with goalkeeper Iker Casillas to return after watching on against France.
"Well, in the first place this it is a very important game for us so Casillas will play," said Del Bosque.
"We know that in these campaigns with qualifying groups, mistakes are very dangerous and there isn't a margin for error.
"We want to start off this tournament well, and not underestimate any national team.
"They haven't won too much, but they have always been a very difficult opponent for their rivals. There has never been much between Macedonia and the team they are playing."
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