Mauresmo is scheduled to meet fifth seed Svetlana Kuznetsova of Russia in the last eight.
Kuznetsova will also know she has to up her game after a hard-fought victory over Pironkova.
She has lost Key Biscayne finals to Kim Clijsters, Svetlana Kuznetsova, Victoria Azarenka and Agnieszka Radwanska.
Kuznetsova said the match was so long she was forgetting the score or who should serve.
Safina's defeat follows the first-round exits of big stars Justine Henin, Maria Sharapova and Svetlana Kuznetsova.
Henin will now play either Svetlana Kuznetsova of Alona Bondarenko who play in the other semi-final.
Henin-Hardenne had 16 winners and 18 unforced errors, while Kuznetsova committed 29 unforced errors with 10 winners.
Germany's Sabine Lisicki and Russia's Svetlana Kuznetsova were also winners, beating Dominika Cibulkova and Nadia Petrova respectively.
But Kuznetsova's compatriot, 10th seed Anastasia Pavlyuchenko, was knocked out of the tournament by Kazakhstan's Ksenia Pervak .
Kuznetsova, meanwhile, will now play fellow Russian Kirilenko after the 30th seed beat Yvonne Meusburger in straight sets.
The Russian was joined in the next round by three former champions: Li Na, Svetlana Kuznetsova and Francesca Schiavone.
But although she managed to capture the opening set, Kuznetsova stepped up a gear to polish off the tie.
Italy can reach their third final in four years on Sunday when Pennetta faces Kuznetsova and Schiavone meets Chakvetadze.
He was joined on the withdrawal list by Thailand's Paradorn Srichaphan and Russian women Svetlana Kuznetsova and Nadia Petrova.
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Kuznetsova then had three game points on her service, but Henin-Hardenne recovered to win the first of six straight games.
Flavia Pennetta and Francesca Schiavone claimed singles wins over Anna Chakvetadze and Svetlana Kuznetsova in Castellaneta Marina in southern Italy.
Schiavone then shocked world number nine Svetlana Kuznetsova 1-6 6-2 6-3 in a match that lasted two hours 21 minutes.
Defending champion Azarenka had to battle through a tough 77-minute first set against Russian Svetlana Kuznetsova, before winning 7-5 6-1.
Clijsters will now play fellow countrywoman Justine Henin-Hardenne , the third seed, who eased past the unseeded Russian Svetlana Kuznetsova 6-1 6-3.
Second seed Svetlana Kuznetsova was also tested, trailing 2-5 in the first set to Bulgaria's Tsvetana Pironkova before triumphing 7-6 (7-0) 6-2.
The Russian, who upset French Open champion Svetlana Kuznetsova in the second round, progressed after beating Slovakia's Dominika Cibulkova 4-6 6-1 6-1.
Wozniacki, seeded 10th, beat Ukraine's Lesia Tsurenko 6-4 6-3 while Kuznetsova overcame Spain's Carla Suarez Navarro in three sets 6-2 4-6 6-3.
In Buenos Aires, Gisela Dulko beat world number nine Svetlana Kuznetsova 6-4 3-6 6-4 to give Argentina the early advantage over Russia .
Second seed Amelie Mauresmo of France beat Tathiana Garbin 6-2 6-1 and US Open champion Svetlana Kuznetsova defeated Czech Eva Birnerova 6-3 6-2.
Russia's Svetlana Kuznetsova , seeded 14, made it safely through to round three after a 7-5 6-3 victory over Spaniard Maria Jose Martinez-Sanchez.
In a match which swung both ways at the Hisense Arena, the final set alone between the 30-year-old and Kuznetsova lasted three hours.
Denmark's Caroline Wozniacki will face Svetlana Kuznetsova of Russia in the last 16 after both women won their third round matches on Saturday.
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