The Chelsea midfielder will lead out England for the second time as the official captain John Terry is not starting against the World Cup winners.
Lampard’s only other match as Fabio Capello’s on-the-field lieutenant was another friendly, against Denmark in Copenhagen, nine months ago which England won 2-1.
Manchester United defender Phil Jones will play in midfield against the Spanish, Capello said.
Lampard has only started just one of this season’s three European Championship qualifiers - against Wales - and was on the substitutes’ bench for the away matches with Bulgaria and Montenegro.
But he has been selected against the Spaniards and was an obvious candidate to lead the side in the absence of the injured Steven Gerrard and out-of-form Rio Ferdinand.
Gareth Barry was the only other major candidate in a youthful England squad containing 11 players who have won six caps or less.