History would heavily favour Williams in the U.S. Open semi-finals on Thursday at Flushing Meadows.
She owns 21 grand slam singles titles, which is 21 more than the other three players combined, and is gunning for her seventh U.S. Open singles trophy while the others are straining to reach their first U.S. final.
Unfancied Italians Flavia Pennetta and Roberta Vinci have also made just one grand slam singles semi-final between them before, while world number two Simona Halep has made the semi-final stage at just two other grand slams.
The 32-year-old Vinci, ranked 43rd, will meet Williams, who has won their four previous meetings, including the most recent last month in the quarter-finals at Toronto.
"She played me really tough, and I didn't really expect that," said Williams, who has won 53 of 55 matches this year and won the Australian, French and Wimbledon titles.
"I'm not going to underestimate her. She played really well. She's not in the semi-finals of a grand slam for no reason. She knows what to do and she knows what to play.
"Definitely a little bit more old school ... it's fun to see people that can still come to the net and still hit slice and still hit one-handers. It's different. It's good for tennis."
Vinci, who has won 25 doubles titles in her career, is 22-20 in singles matches and without a singles title this season.
She is already thrilled by her performances in New York.
"I think I'm at the end of my career, so my semi-final, first (slam) semi-final, it's incredible," said the 32-year-old.
"I'm very proud of myself. I have nothing to lose, just play my game.
"I know that I have a lot of experience, but when you play against Serena doesn't matter.
"You have to play better, then better, then better."
Pennetta, 33, also draws a difficult assignment against Halep. The Italian has a 3-1 career edge, but lost 6-3 7-5 in their last encounter earlier this year in Miami.
The veteran said she would not overlook the power of the short, quick-footed Romanian, who she rated as more powerful than former world number one Victoria Azarenka, who fell in three sets to Halep in the quarter-finals.
"To make a winner to her you have to finish the point seven times," Pennetta said. "She's always there, always in - the ball always comes back."
Halep, who has won three times this year, lost in the second round at the French Open, where she was runner-up in 2014, and beaten in the first round at Wimbledon.
That led her to take a hiatus before rediscovering her form on the hardcourts running up to the U.S. Open.
"I don't have big muscles. I'm not tall. I have power inside," Halep said. "I fight.
"Every point is a big challenge. I do everything I can. I run for every ball, and that makes me stronger in this moment."
(Editing by Greg Stutchbury)
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