She won a decisive match in the final Italy vs Belgium against Kirsten Flipkens allowing her national team to win the 2006 Fed Cup.

Santangelo reached the fourth round at the 2004 Australian Open, defeating 16th-seeded Magüi Serna, Barbara Schett, and 19th-seeded Eleni Daniilidou—losing to eventual champion and world No.

She and her Italian teammates Francesca Schiavone, Flavia Pennetta, and Roberta Vinci beat the Belgian team 3–2 in the 2006 Fed Cup final.

In Doha during the second round, Santangelo faced fellow countrywoman Francesca Schiavone, and led 6–4, 6–6 (6–5), but lost 6–4, 6–7, 0–1 ret., after dropping a match point.

During the clay court season, Santangelo defeated Nadia Petrova in the second round of Warsaw, for her second career top-10 victory, reaching her third quarterfinal of the year.

Santangelo returned from eight-month left foot injury lay-off in May; she reached the second round twice (including the 2008 Wimbledon Championships) and she won two ITF tournaments, Biella and Ortisei.

In 2009, once again plagued by her foot injury, Santangelo won three doubles tournaments, all of them partnering Nathalie Dechy: Auckland Open where they defeated Nuria Llagostera Vives and Arantxa Parra Santonja, the Monterrey Open with a two-sets win over Iveta Benešová and Barbora Záhlavová-Strýcová and, finally, Strasbourg, defeating Claire Feuerstein and Stéphanie Foretz with a 6–0, 6–1 score.

On 6 September, partnering Laura Olivieri, she won the 2009 European Beach Tennis Championships with a straight-sets win over the defending champions, Simona Briganti and Rossella Stefanelli.

[2] In May 2010, Santangelo announced her decision to compete in doubles events only, citing her recurrent left foot injury as the main cause that persuaded her to renounce to play singles matches.