Without Chris Bosh for the first time in the NBA playoffs, championship favourites Miami suddenly looked vulnerable as they fell to an upset 78-75 defeat to the Indiana Pacers that left their Eastern Conference semi-final series tied at 1-all.
Bosh has been ruled him out indefinitely after picking up an abdominal strain in Game One on Monday and questions are being asked about how effective the Heat can be without one of their key components.
He missed nine games during the season and the Heat were just 4-5 without him.
David West top scored for the Pacers with 16 points.
James led Miami with 28 points and nine rebounds and Wade put up 24 points and made six rebounds.
The series moves to Indianapolis for Game Three on Friday.
Elsewhere the San Antonio Spurs drew first blood against the Los Angeles Clippers with a 108-92 victory in Texas to take a 1-nil lead in the best of seven series.