Fernando Jubero's Guarani surrendered top spot in Clausura after they were beaten 3-2 by 3 de Febrero last week.
But Guarani returned to the summit thanks to goals from Ivan Gonzalez and Fernando Fernandez.
Guarani have collected 24 points from 12 matches, two more than in-form Cerro Porteno, who have a game in hand after their 3-1 victory at home to General Diaz on Sunday.
12 de Octubre - second-bottom in the table - went into Monday's fixture at Estadio Rogelio Lorenzo Livieres in the midst of a four-game winless streak.
And their poor form showed as Gonzalez opened the scoring in the 17th minute.
12 de Octubre, though, appeared on track for a share of the spoils after Wildo Alonso levelled proceedings with 11 minutes remaining.
However, 12 de Octubre's joys were short-lived as the home side restored their lead just a minute later courtesy of Fernandez.
Cerro Porteno extended their winning streak to five matches at the expense of General Diaz.
Visiting General Diaz had no answer, with Mauricio Sperduti, Oscar Romero and Jose Ortigoza on target for Cerro.
Blas Caceres did pull a goal back in the 71st minute, but it was nothing more than a consolation.
In other results, Libertad returned to winning ways thanks to a routine 3-0 win over rock-bottom Sol de America, while Silvio Torales scored twice as fifth-placed Nacional Asuncion held on to beat 10-man Deportivo Capiata 3-2.
Olimpia's winless streak extended to three matches after they lost 1-0 at home to 3 de Febrero and Sportivo Luqueno overturned a two-goal deficit to earn a 2-2 draw at Rubio Nu.
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