Also on Tuesday, a Democratic candidate fell 3 percentage points short of defeating a Republican in the race to fill budget director Mick Mulvaney's House former seat in SC.
The nearest Republican was Georgia's former secretary of state Handel with just 19.8 per cent - but in a field split by numerous party's candidates.
The lesson for Democrats is that anti-Trumpism is not enough, at least not at this point.
Many political pundits have suggested that the widely held perception of Pelosi as a Washington insider and a San Francisco liberal might not be beneficial to Democrats seeking office in blue-collar and/or Republican-leaning congressional districts.
"I worry sometimes that we get so obsessed and angered by Donald Trump, which is OK, but you can't hold on to it because it takes your eye off the ball", Ryan said. Plus, the Republican-controlled House is perhaps just slightly more popular than Katy Perry's new album or The Mummy right now, and Handel is joining that team. But despite all the money, the Democratic Party didn't turn the tables in special elections for house seats vacated by Republicans. In Kansas in April, in Montana last month and in Georgia and SC on Tuesday, Democratic candidates outperformed their party's past showings, but still fell short where it counts: Republicans won.
House Democratic leaders are taking some comfort in coming in a close second for a seat that's always been firmly in GOP hands.
Also, in the past three midterm elections, more than 80 percent of voters who disapproved of the president voted against his party in House races.
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Asked if that meant Pelosi should go, Moulton - who backed Ohio Rep. Tim Ryan's challenge to Pelosi's leadership post past year - said: "I think that's a question for the caucus to decide".
Ossoff told his supporters: "The fight goes on". The Republican won a key contest in Georgia. Most recently, Tom Price resigned in February to join Trump's administration.
Ms Karen Handel with her husband Steve after her election victory on Tuesday. And it could be that Ossoff, a documentary filmmaker and former congressional staffer, didn't appeal to residents because even though he grew up in the district, he now lives in Atlanta - several miles outside the district. She pointed voters instead to her "proven conservative record" as a state and local elected official.
The outcome also raised questions about the future of House Democratic leader Nancy Pelosi.
In the same district just seven months later, Democrat candidate Jon Ossoff garnered 124,893 votes, but spent more than $23 million to do it. The Republican campaign establishment, however, helped make up the difference.
"It's time for change, and personally I think it's time for a new generation of leadership in the party", U.S. Rep. Seth Moulton (D-Salem) told reporters on Capitol Hill yesterday, though he stopped short of explicitly calling for Pelosi's ouster.
On policy, Handel mostly echoes the GOP line. "But she certainly is one of the reasons".