Wednesday's debate focused on the issue considered by voters to be the most crucial of the election -- the economy.
Romney "has to paint a compelling picture of a better economic future and why he can lead us there and President Obama can't," said GOP pollster Whit Ayres. Democratic pollster Peter Hart made a similar point, saying "if Romney loses this issue, then he is toast."
Jim Lehrer of PBS moderated his 12th presidential debate. He previously announced that the 90-minute event would include three segments on the economy and one each on health care, the role of government, and governing leadership and style. Each segment was scheduled for 15 minutes.
The two candidates shook hands and shared a laugh after being introduced by Lehrer as the audience applauded before being asked to remain silent for the remainder of the debate.
Organizers hoped the segmented format, with candidates given two minutes to answer questions, would allow for a more free-wheeling discussion instead of a series of rehearsed sound bites.
The other presidential debates will occur on October 16 in New York and October 22 in Florida. Vice President Joe Biden and Rep. Paul Ryan of Wisconsin, Romney's running mate, will debate on October 11 in Kentucky.
CNN's John King and Amy Roberts contributed to this report.