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Probably Eleanor Roosevelt
Undoubtedly Jacqueline Kennedy (Onassis)
_________
Many first ladies have been highly regarded for their effective role as White House hostess; beginning with Dolley Madison, and including Harriet Lane (bachelor Buchanan's ward) and Lucy Hayes. Several have been active and thought to be personally inspiring (such as Jackie Kennedy and Betty Ford). A number are praised for their separate accomplishments (e.g., overseeing renovations to the White House, or separate championing of some cause).
But if "influential" refers to helping shape the President's policies, the most influential group would be those who were close political advisors to him. The most notable of these, in no particular order: Edith Wilson (who virtually acted as President after her husband's stroke!), Eleanor Roosevelt, Hillary Clinton, Rosalynn Carter, Sarah Polk.
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