Rapper friend Drake and fellow singer Justin Timberlake were among those rooting for her on Centre Court.
To make the potential bad omen even scarier, the 2015 loss was to Roberta Vinci, an Italian, and Williams this week was facing Italy's Camila Giorgi. But Serena, who has only lost 10 points on her serve so far, will be serving for the match. She seemed undaunted by the stage or the opponent.
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Sometimes I feel I am in trouble. For whatever reason, I was so calm.
"I would hope she doesn't play tennis", she said. "I don't know why all the seeds are gone". It is what it is'. But it never happened to me that the umpire changed the decision. I can't describe it. I just kept fighting. "This is only my fourth tournament back", she said.
"Maybe I'll tweet at him if I win on Wednesday", Isner said. But that's okay. "I have faced a thousand and three seeds in my life, so I'm ok", she reassured one inquisitor during her media conference.
But, hitting her serve with more ferocity, Serena wrestled back control of the match with a crucial break in the fourth game of the second set. Everything from that point on seemed to click for Williams. German made six breaks and lost four games on his serve.
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The top-ranked Spaniard beat Jiri Vesely, 6-3, 6-3, 6-4, on Centre Court to return to the last eight for the first time since he was runner-up to Novak Djokovic in 2011.
With every passing round Williams has grown in strength and confidence.
With two players that possess as much firepower, especially on serve as the Czech and the Dutchwoman, there didn't figure to be a lot of break chances, but it was Bertens who had the first opportunity. "Today was tougher than the scoreline suggested".
"And it's interesting because I don't even scout as much because when I watch them play, it's a totally different game then when they play me".
Williams hit six of her seven aces in the final set, including one clocked at 122 miles per hour, and won 44 of the last 54 points she served. She is yet to drop a set this year. Serena loses when you are around.
The 2017 French Open victor stormed into the last eight for the first time at The All England Club with a 7-6 (7-4) 6-0 victory in the first of 16 fourth-round singles encounters on so-called Manic Monday at Wimbledon. "That was four or five weeks ago", she said. That doesn't matter. This is a whole new match, it's a new surface, it's everything. We're starting from zero. "Each of us, seeded or not, we're just here to do our best".
However, Williams lifted her intensity to level, before closing out the match to move a step closer to reclaiming the title she won in 2016.