Internationally, Pepe opted to play for Portugal, representing the nation at four FIFA World Cups and five UEFA European Championships.

At age 18, alongside teammate Ezequias, he moved to Portugal to sign with Marítimo in Madeira, spending the vast majority of his first season with the B-team.

After being promoted to the main squad for the 2002–03 season, under Ukrainian manager Anatoliy Byshovets, Pepe rarely missed a match, playing in several positions including defensive midfielder.

However, neither club could agree on financial terms and the negotiations broke down, with the player returning[7] and going on to help Marítimo finish sixth in the following campaign and qualify to the UEFA Cup, having contributed with 1 goal in 30 matches.

However, in the following year, under the guidance of Co Adriaanse, he had a breakthrough season, establishing himself as one of the best defenders in the domestic competition: the Dutchman often chose a 3–4–3 offensive system, with the player often pitched as the only natural stopper.

As Los Blancos were eventually crowned champions of La Liga, he delivered a Man of the match performance in a 1–0 win at the Camp Nou against Barcelona.

On 21 April 2009, he was also involved in an incident with Getafe's Javier Casquero: with the score at 2–2 and only a few minutes to play, he brought down the midfielder in the penalty area, being subsequently sent off.

In the ensuing mêlée, he also struck another opposing player, Juan Ángel Albín, in the face and eventually received a ten-match ban, which effectively ended his season.

On 4 October 2009, he scored his first goal in the league, against Sevilla at the Ramón Sánchez Pizjuán Stadium, heading home from a Guti free-kick in a 1–2 loss.

However, on 12 December, during a match at Mestalla against Valencia (3–2 win), he landed awkwardly following an aerial challenge and was stretchered off the pitch in the dying minutes of the first half.

[15] According to the newspaper, "[W]hen he signed for Real Madrid in 2007, he sacrificed a part of his salary to pay for his huge transfer fee – this made him one of the lowest earners at the club, making €1.8 million a year.

[19] Pepe spent the final stretch of the season appearing as a defensive midfielder as Real Madrid faced Barcelona four times in less than one month.

On 27 April 2011, in the UEFA Champions League semi-final first leg, he was sent off for a controversial challenge on Barcelona defender Dani Alves in an eventual 0–2 home loss.

[22] The verdict was announced eight days later: the red card stood and Pepe therefore received a one-match ban from European competition, which he served by not playing in the 1–1 draw in the second leg at Camp Nou.

[25] In the first match of the Copa del Rey quarter-final against Barcelona on 18 January 2012, he stamped on the hand of Lionel Messi, who was on the ground after having been fouled.

[30][31] On 21 March 2012, Pepe was involved in another serious incident: after a 1–1 away draw against Villarreal in which he was booked and Real Madrid finished with nine players, he confronted referee José Luis Paradas Romero in the locker room area, saying, "What a ripoff motherfucker.

[34] On 19 August 2012, in the league opener against Valencia, Pepe collided with Real Madrid goalkeeper Iker Casillas in the play that led to the visitors equalising the score 1–1 (the final result).

[36] Amid feuds with Mourinho, Pepe lost his starting place to Raphaël Varane throughout the season and would end up getting into a scuffle with Atlético Madrid manager Diego Simeone from the substitutes' bench in the 2013 Copa del Rey Final.

He started the match when the team won the Champions League final against Atlético Madrid in a penalty shoot-out at San Siro, Milan.

[43] Turkish Süper Lig side Beşiktaş announced the signing of Pepe on a free transfer from Real Madrid, on 4 July 2017.

[54] On 7 November, in the return fixture, Pepe headed in Porto's second goal in a 2–0 victory over Royal Antwerp, becoming, at 40 years and 254 days old, the oldest ever goalscorer in the UEFA Champions League history, breaking the record previously held by Manfred Burgsmüller in 1988.

However, according to the player's father, in 2006, he was contacted by head coach Dunga about a possible call-up, which he declined, stating that once he obtained Portuguese citizenship, he would join its national team.

[59] An injury while training for his club prevented the debut for his adopted country, which would materialise almost four months later, in Portugal's last match in the tournament against Finland on 21 November, a 0–0 home draw.

Again a starter in Euro 2012 under manager Paulo Bento, Pepe opened the score in the second group game against Denmark, heading home after a João Moutinho corner kick in an eventual 3–2 win.

[61] He was later chosen by UEFA as man of the match[62] and, in the semi-final, he was one of two Portugal players to score in a 2–4 penalty shootout defeat to eventual winners Spain.