The 2010 world champions were dethroned in such ignominious fashion in Brazil, crashing out in the group stage, but were far too powerful for their opponents in their first competitive fixture since returning from South America.
Vicente del Bosque's side were on the receiving end of a 5-1 scoreline against Holland in their opening World Cup game and one of the villains that night, centre-back Sergio Ramos, got them up and running against Macedonia with a cool Panenka penalty after 16 minutes.
Spain are still the European champions and doubled their lead just a minute later when Paco Alcacer, on his home ground, marked his first competitive game for his country with a goal.
Agim Ibraimi pulled one back from the spot for the visitors shortly before the half-hour mark, but thoughts of an upset were quickly dashed.
Sergio Busquets added a third on the stroke of half-time and second-half goals from David Silva and Pedro wrapped up the win.
Elsewhere in Group C, Ukraine suffered a shock 1-0 defeat at home to Slovakia, Robert Mak with the winner in the 17th minute.
There was a surprise in Luxembourg as well as the hosts held Belarus to a 1-1 draw.
Lars Krogh Gerson put the hosts ahead three minutes before the break and they led until the 78th minute when Stanislav Dragun equalised.
Like Spain, England also endured a miserable World Cup and they too responded in impressive fashion in their Group E opener as a second-half brace from new Arsenal signing Danny Welbeck earned a 2-0 win over Switzerland in Basle.
Estonia left it late to beat 10-man Slovenia, substitute Ats Purje with the winner four minutes from time after Dalibor Stevanovic had been sent off in the 80th minute.
In the same pool Lithuania won 2-0 in San Marino thanks to goals from Deividas Matulevicius and Arvydas Novikovas.
Russia, who also failed to live up to expectations in Brazil, set the early pace in Group G following a 4-0 win at home to Liechtenstein, although they were given a helping hand by their opponents.
The visitors scored two own goals to put Russia 2-0 in front, Martin Buchel putting through his own net after four minutes and Franz Burgmeier following suit five minutes after the break.
A Dmitri Kombarov penalty five minutes later made it three before Artem Dzyuba completed the scoring.
Montenegro also got off to a winning start, seeing off Moldova 2-0 thanks to goals from Mirko Vucinic and Zarko Tomasevic.
Austria and Sweden drew 1-1, David Alaba putting the Austrians ahead with a seventh-minute penalty and Erkan Zengin equalising five minutes later