Cerro Porteno led by three goals at half-time thanks to a pair of penalties from attacking midfielder Julio dos Santos and Daniel Guiza's strike and although 12 de Octubre hit back with a spot-kick of their own in the second half, the title-holders held on for victory.
The win on the opening weekend of the Apertura season took Cerro Porteno into second position in the standings, behind only Nacional Asuncion, who won 3-0 against Sportivo Luqueno.
Nacional claimed last year's Apertura title, while Cerro Porteno took out the Clausura championship.
In Itaugua, Cerro Porteno silenced the home crowd early with Dos Santos converting a penalty in the 17th minute.
Guiza made it 2-0 in the 25th minute before Dos Santos again slotted a spot-kick seven minutes before half-time.
Just after the hour-mark, Willian sent Cerro Porteno's goalkeeper the wrong way from the spot to drag 12 de Octubre back into the contest but the home side could not get closer to the Clausura champions.
In Asuncion, Nacional moved to the top of the ladder with a comfortable win over Luqueno.
An own goal from Luqueno defender Julio Irrazabal put the hosts on their way after 16 minutes, before second-half goals from Julio Santa Cruz and Derlis Orue wrapped up Nacional's victory.
A plus-three goal difference put Nacional in the outright lead, ahead of Cerro Porteno, Olimpia and Libertad, who all have a goal difference of plus two.
Olimpia opened their campaign with a 3-1 win away to General Diaz, while Libertad defeated Guarani 2-0.
In other opening round results, 3 de Febrero drew 0-0 with Deportivo Capiata and Sol de America came from behind twice to claim a 2-2 draw with Rubio Nu.
