David Silva was the star man for the reigning European champions as they brushed aside minnows Macedonia in the Group C clash at the Estadio Ciudad de Valencia.
The Manchester City schemer played a part in three of his side's goals, first winning the penalty from which Sergio Ramos dinked home the opener.
Valencia striker Paco Alcacer then grabbed a debut goal at the home of rivals Levante to make it 2-0.
Agim Ibraimi's penalty halved the deficit by scoring from the spot, but Sergio Busquets' maiden international goal in his 69th appearance on the stroke of half-time re-opened Spain's two-goal lead.
Silva was rewarded for his outstanding showing by drilling home Spain's fourth five minutes after the break, and Cesc Fabregas hit the crossbar before Pedro rounded off the win with a delightful lofted finish from another Silva assist in the closing stages.
Elsewhere in Group C, Robert Mak's goal gave Slovakia a valuable three points in a 1-0 win in Ukraine, while Luxembourg gained a point in a 1-1 draw at home to Belarus.
In Group E, England stole the early initiative as a second-half double from Danny Welbeck downed Switzerland at St Jakob-Park in Basle.
The match should represent England's biggest challenge of the pool, and manager Roy Hodgson was delighted when Welbeck opened up a tense affair by finishing at the back post after splendid work from Wayne Rooney and Raheem Sterling.
Josip Drmic thought he had equalised for Switzerland when he rounded Joe Hart and shot towards goal, but he was denied by a terrific last-ditch block from Gary Cahill.
England then rounded off the win deep into injury time, as Rickie Lambert picked out Welbeck in the area and the new Arsenal signing showed good composure to finish past Yann Sommer.
Estonia also started Group E with a victory, Ats Purje's 86th-minute winner sinking Slovenia in a 1-0 triumph, with the visitors not helped by Dalibor Stevanovic's red card. Rounding off the group, Lithuania were 2-0 winners in San Marino.
Zlatan Ibrahimovic earned his 100th cap for Sweden in their 1-1 Group G draw in Austria.
The Paris Saint-Germain forward, who became his country's record goalscorer in the 2-0 friendly win over Estonia last Thursday, laid on the assist for Erkan Zengin to cancel out David Alaba's early penalty.
However, Ibrahimovic was lucky not to be sent off later in the game when he appeared to elbow Alaba in the face.
Also in the pool, Russia benefited from two own goals and a penalty from Dmitri Kombarov as Fabio Capello's men beat Liechenstein 4-0, Artem Dzyuba rounding off the scoring in the 65th minute.
Montenegro were also winners in Group G, with goals from Mirko Vucinic and Zarko Tomasevic enough to defeat Moldova 2-0.
