The referendum takes place this weekend, and The Carter Center, headquartered in Atlanta, said the deadline for applying for accreditation was too tight.
"The late release of regulations for accreditation of witnesses precludes the center from conducting a comprehensive assessment of all aspects of the referendum process, consistent with its methodology for professional observation of elections," the organization said in a written statement.
The Carter Center had a team of nearly 40 "witnesses" on the ground in Egypt during the 2011 parliamentary elections and about 100 for this year's presidential vote. Their goal was ensure the voting was fair and transparent.
The referendum votes taking place Dec. 15 and 22 will determine the fate of draft constitution that opponents contend restricts freedoms and gives Islamist parties too much political influence.
Politics have been anything but calm in Egypt this winter with Islamists and Morsi supporters squaring off in the streets.
Human Rights Watch Thursday demanded the public prosecutor investigate the detention and videotaped beating of dozens of Morsi's foes by Islamist supporters earlier this month.
A spokesman said the incidents cast doubt on Morsi's contention the protesters were paid instigators.