A similar challenge succeeded in knocking off former Indiana senator Richard Lugar in 2012, despite - or because of - his 35 years in Congress.
Landrieu's office and campaign are fighting back very cautiously.
“I have lived at my home on Prieur Street (New Orleans) most of my life and I live there now when not fulfilling my duties in Washington or serving constituents across the state,” Landrieu said in a statement released to ABC News.
A Landrieu campaign official also noted that both Landrieu and her husband file taxes in Louisiana. Her campaign did not elaborate further.
It is an issue that is increasingly being employed this year against members of Congress who are repeatedly reelected, and spend most of their time in Washington.
Landrieu, a Democrat, is already in a race that is considered one of the most closely contested this year and could determine control of the Senate.
Landrieu maintains that she lives at her parents’ home in New Orleans, of which she is a partial owner under a family trust and where she is registered to vote.
According to the Louisiana Secretary of State’s listed qualifications, a candidate for U.S. Senate must “be an inhabitant of Louisiana when elected.”
The Constitution governs residency requirements, broadly. As Louisiana’s law is worded, it requires senators to “be an Inhabitant of that State in which he shall be chosen.”
The definition of what it is to be “an inhabitant” is a broad one, said Dr. Pearson Cross, the head of the political science department at the University of Louisiana. From a legal standpoint, he said it would be difficult to prove that Landrieu is not an inhabitant.
“Courts have been reluctant to intervene in that and have given a lot of latitude in defining residency,” Cross said. “To say that Mary Landrieu is not a resident is a bit disingenuous given that Senate and Congress have become a full-time occupation and that their work is done in Washington.”
Cross said the issue of Landrieu's residency is a ploy likely to influence voters who are already inclined to vote against Landrieu.
“It will have resonance with some voters who are pre-inclined to believe,” Cross said. “It will probably have little effect on voters who aren’t inclined to believe it. In terms of Louisiana politics, it’s clear that many people, particularly those with national focus, are running against Washington. To the extent that you can tar someone with the Washington brush, it’s an effective campaign tactic.”
This story has been updated.