Anna Tuthill Symmes Harrison had opposed her husband's candidacy for President, remarking, "I wish that my husband's friends had left him where he is, happy and contented in retirement." Yet the appeal of running the hero of Tippecanoe against Martin Van Buren was too much for the Whig Party to pass up, and Harrison's popularity netted a landslide victory. Resigned to her fate and suffering from poor health, Anna Harrison chose to forego her husband’s inauguration. Daughter-in-law Jane Irwin Harrison assumed hostessing duties in the interim, as Anna resolved to set out for Washington when the roads improved.

She would never make the trip. On April 4, 1841, four weeks to the day after his inauguration, William Henry Harrison died, even as his wife was packing to join him.

While never a First Lady, Anna Harrison was the first presidential wife widowed while her husband was in office. Because of her status as a presidential widow, Congress awarded Anna a $25,000 award as well as the franking privilege, allowing her to send mail free of charge. Although pleased with such honors, she was not happy with John Tyler assuming leadership of the Whig party. Nonetheless, Anna Harrison used her position as presidential widow skillfully, persuading Tyler to tap her family members for political appointments.

It is difficult to comment on how Anna Harrison would have fulfilled her duties as a presidential spouse. Little is known about her, except that she was familiar with current political issues and forbade her husband from campaigning on Sundays. She opposed slavery, had survived the rigors of military life on the frontier, and had used her political contacts to benefit her family. Powerful as a presidential widow, one can only wonder what her legacy as a presidential spouse might have been.