In 1898, he ran for prosecutor of Jackson County, with political and financial support from Democratic Party boss James Pendergast.

In the debate over the Immigration Act of 1917, he declared that "no man not of the white race ought to be permitted to settle permanently in the United States of America.

Later in his political career, Reed opposed the Ku Klux Klan particularly in his reelection campaign of 1922, which cost him numerous votes.

In 1927, he opposed the reauthorization of the Sheppard–Towner Act, which had been enacted in 1921, to reduce maternal and infant mortality and improve the health of mothers and babies, and he attacked the Children's Bureau for its "excessive" federal funding and the "power and control" Sheppard-Towner gave to Grace Abbott, Bureau Chief.

[12] The Sapiro case ended in a mistrial after which Henry Ford agreed to settle the matter by paying a significant amount of money to the plaintiff.

[13] During the trial, he discovered that his neighbor and married mistress, Nell Donnelly Reed, was two months pregnant with his child.

[15] Reed closely involved himself in the case and was alleged to have called upon the assistance of John Lazia, a major figure in the Kansas City, Missouri organized crime scene, to help find Donnelly, which occurred within 34 hours of the abduction.

[16] The subsequent court cases led to three men being imprisoned for the crime and to the controversial acquittal of a fourth, who claimed to have thought that he was abducting someone else.

[1][15] He died just two days short of his son's 13th birthday after he had caught pneumonia after spending a morning fishing in the rain.

J. Michael Cronan, James A. Reed: Legendary Lawyer; Marplot in the United States Senate, iUniverse Press (Bloomington, IN, 2018)