"Unfortunately, I have to withdraw from Madrid because I've been battling the flu and I'm not at 100%," Williams, who won the event in 2012 and 2013, told the WTA's website. "I look forward to returning soon."
Her withdrawal comes less than a month before the start of the French Open, where the American is the defending champion.
Concern among her supporters -- not to mention the WTA -- is sure to escalate if the 34-year-old doesn't show up at next week's Italian Open
Federer in
But there was better news for organizers when men's 17-time grand slam champion Roger Federer confirmed that he would be playing in the Spanish capital.
He added Miami -- where illness ultimately derailed him -- Monte Carlo and now Madrid to his schedule.
"Federer is one of the best players in history," Manolo Santana, a director at the tournament and four-time grand slam singles champion, told the Madrid Open's website. "We are delighted to have him back in the Caja Magica. In addition, he is one of the fans' favorites because of everything he has achieved in his career.
"We will be welcoming him with open arms."
Madrid could see home hope if Rafael Nadal and Novak Djokovic tangle for the first time during this clay-court swing.
Nadal won Monte Carlo and Barcelona in successive weeks after slumping -- by his standards -- for most of 2016. Djokovic is the world No. 1 and French Open favorite. The Serb has captured four of the past five majors.