Ms Harris immediately pressed the Democratic case better than President Joe Biden did before he stepped aside as a candidate, hitting the former president's proposed tax cuts and tariffs and Republican efforts to restrict abortion access.
Mr Trump in turn tried to link Ms Harris to Mr Biden, questioning why she had not acted on her proposed ideas while serving as vice president.
Ms Harris walked up to her rival's lectern to introduce herself as the debate opened.
"Kamala Harris," she said, extending her hand to Mr Trump, who received it in a handshake.
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