Rendell made the comment Tuesday at a meeting of the National Governors Association in Philadelphia that featured President-elect Barack Obama.
Rendell said Napolitano is "perfect for that job. Because for that job, you have to have no life. Janet has no family. Perfect. She can devote, literally, 19-20 hours a day to it."
Napolitano, a second-term governor, former state attorney general and former U.S. attorney, has never been married and has no children.
Napolitano's spokeswoman, Jeanine L'Ecuyer, said the Arizona governor described Rendell as a good friend and had little to say about his remarks.
"She said she really appreciates Gov. Rendell's confidence in her and the confidence of the president-elect," L'Ecuyer said.
L'Ecuyer deflected questions about whether the comment could be construed as sexist.
"There's a lot of people weighing in on that. We'll leave it to you guys to do that," she said.
Rendell press secretary Chuck Ardo said Rendell meant no disrespect to Napolitano and would have made the same comment if the appointee was a man.
"Ed Rendell has got a long, well-documented history of supporting equality amongst the sexes, amongst the races," Ardo said. "If this comment is interpreted in any way other than referring to the demands of the office, it is being misinterpreted."
Ardo said he did not know who Rendell was speaking with at the time.
In a similar incident nearly four years ago, a leading Arizona state senator apologized to Napolitano after making light of her status as a lawyer and person without a family.
Senate President Ken Bennett was critical of Napolitano's positions regarding lawsuit reform and family values.
"She's a lawyer, and she doesn't have a family," Bennett said at the time. He later called the governor to apologize.