Reed, a former executive director of the Republican National Committee who ran Sen. Bob Dole's presidential campaign in 1996, worked as the Chamber's chief political adviser for more than a decade, helping to spend more than $100 million to back mostly Republican candidates.
But at the beginning of September, the country's largest business group decided to endorse 23 freshmen House Democrats in the November elections (in addition to 29 freshmen House Republicans), exacerbating internal divisions and prompting fierce pushback from the group's GOP donors.
“I can no longer be part of this institution as it moves left,” Reed told Politico.
He said his decision to leave was linked to the Chamber's reluctance to spend heavily on Senate races in the final weeks of the 2020 election, as Democrats look to flip the congressional upper chamber.
“They would not let me spend Senate money down the home stretch,” Reed said.
But the Chamber rebuked that version, saying it had fired Reed "for cause."
"An internal review has revealed that Reed repeatedly breached confidentiality, distorted facts for his own benefit, withheld information from Chamber leadership and leaked internal information to the press," a Chamber spokesperson told FOX Business. "We have the documentation of his actions and it is irrefutable."
The Chamber has a track record of supporting Republican candidates, but the once reliably pro-GOP organization has shifted course amid signs that Democrats will maintain control of the House -- and possibly win a majority in the Senate. By donating to Democratic candidates, the lobbying group can keep a line of communication with some of the party's more moderate members.
When determining which candidates to endorse, Chamber leadership uses a formula that scores members based upon how their voting record aligns with its priorities. A lawmaker needs to receive a score of at least 70% in order to be endorsed by the Chamber.
Earlier in the year, the Chamber spent six figures on digital ads opposing the reelection of Rep. Alexandria Ocasio-Cortez in a primary the New York Democrat won.
The majority of spending by the Chamber so far this year has gone toward helping Republicans, according to data compiled by the non-partisan Center for Responsive Politics.
Fox News' Marisa Schultz contributed to this report