Two internationals arrived at the club from Valencia CF, who had been fourth in the summer of 1950 with the Spanish team in the 1950 World Cup in Brazil. They were striker Silvestre Igoa and goalkeeper Ignacio Eizaguirre. The Madrid-Ciudad Real line was a Spanish railway line that was in operation between 1879 and 1988. The route was of Iberian gauge, had a length of about 175 kilometers and allowed the direct rail link between Madrid and Ciudad Real. In addition, Julen Lopetegui's team became the first team to win its first 6 European finals (all from UEFA), surpassing the five that Madrid won in the European Cup. Germany is a powerful team, with players of the highest level, and their name is written in the history of the World Cup", and in 2013 Santa Cruz also told Telefuturo that Chilavert's comments were false because more than ten years after the incident. In the second game on July 9, Santa Cruz's first goal for Paraguay came after 54 minutes in their 2-2 draw against Brazil in Córdoba. Santa Cruz was part of Paraguay's starting eleven for the 2011 Copa América. On July 3, he played in the first match of the group stage, a 0–0 draw against Ecuador.

On June 30, Santa Cruz plays in the starting 11 but before half an hour into the game, coach Ramón Díaz was forced to replace him due to a thigh injury, being the second change due to injury of the game (the first was Derlis Gonzales), Paraguay would lose 6-1 and Santa Cruz would miss the final game of the tournament against Peru for third place on July 3. Santa Cruz was doubtful for the 2006 FIFA World Cup as he had been recovering from a knee injury, however he recovered in time for the start of the tournament and was eventually selected in the 23-man roster by the coach Anibal Ruiz. Despite the injury he was a substitute in the team's opening game against champions Italy, Santa Cruz went on to start the next 2 group F matches, Slovakia and New Zealand, he was chosen as the "Man of the Match". On July 13, Santa Cruz then played just 39 minutes of Paraguay's final group game against Venezuela before being replaced by Nelson Haedo Valdez.

Santa Cruz also stated that what had been said was painful because he and Chilavert had shared many experiences, but people had seen Santa Cruz play and were aware of his professionalism. On June 16 he was man of the match in a 1-0 win over Jamaica, and on June 20 against Uruguay he would come on in the second half to replace the injured Lucas Barrios in a 1-1 tie. Paraguay would advance to the quarterfinals after finishing second in the group with 5 points behind Argentina with 7. On June 27, he would play the quarterfinals against the leader of group C, Brazil, a match where Santa Cruz was fouled inside the area, achieving a penalty in favor of Paraguay with Derlis Gonzales equalizing the match 1-1. With 90 minutes even, they went to the penalty shootout where Brazil had missed 2 of 4 and it was Roque's turn to shoot, but he would miss his shot, even so, Paraguay advanced to the semis after winning 4 – 3 on penalties and they would face their rival in the group stage, Argentina. Santa Cruz was part of Paraguay's starting eleven for the 2015 Copa América, where Paraguay was in group B accompanied by Argentina, Uruguay and the guest Jamaica.

Santa Cruz was selected for the 2007 Copa América under new coach Gerardo Martino. On June 7, 2013, Santa Cruz scored in a 2–1 home loss against Chile during a 2014 FIFA World Cup qualifying match. The goal raised his tally to 26, which made him the all-time leading scorer in the history of the Paraguayan team. On November 18, 2014, Santa Cruz scored in a 2-1 friendly away loss against Peru in Lima, bringing his tally to 30 goals for the national team. Santa Cruz scored four goals during 2006 FIFA World Cup qualifying. The first came in a 2-1 home win against Ecuador on November 15, 2003, fc barcelona jerseys when Santa Cruz had given up a 1-1 lead. 0 at 29 minutes. Santa Cruz played 83 minutes of the game before being substituted off the field for Pablo Zeballos. The main double-shot staircase was built around 1525, when the primitive houses of Pedro de Sotomayor were transformed into a palace, in a corner of the patio and inside a wall box that was originally diaphanous, open to the patio.

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