Reigning champion Carlos Ortiz of Mexico and Argentina's Emiliano Grillo withdrew from the PGA Tour's Houston Open on Tuesday.
Ortiz pulled out due to a left shoulder injury, saying he has been struggling with a sore shoulder since a trip to Japan last month.
"I went to the doctor this morning and he recommended that I not play and I take time to recover," Ortiz said.
"So I think I'm going to take his advice... so I can start healthy in January."
Ortiz withdrew from the Zozo Championship in Japan three weeks ago with the shoulder injury.
But Ortiz finished second last week at the Mayakoba Championship in Mexico, his best showing since taking his only PGA title last year at Houston.
"This is incredibly disappointing to me as I was looking forward to defending my first PGA Tour title," Ortiz said. "I'm honoured to be a champion of this event and I look forward to returning next year."
Ortiz and Grillo were replaced in the field by Americans John Huh and Max McGreevy.
Players from outside the United States have won five consecutive US PGA titles, one shy of the matching the longest such runs on record from 2004 and 2008.