"I think it has created an image of him as not being up to this task," Rove said on Fox News. "That’s really deadly."

But Cain said that the Republican strategist was biased against campaigns with big organizations and large fundraising totals.

"What has Karl Rove done?" Cain said. "If I become the nominee, he has given Democrats talking points for a commercial to attack me. It makes no sense unless it's a deliberate attempt on his part to try to push me down so that the candidate he wants rises to the top."

Cain is not the first Republican candidate to earn Rove's criticism. In September, Rove said that Texas Gov. Rick Perry's position on Social Security — repeatedly calling the program a "Ponzi scheme" — was "toxic" to his candidacy.