The 1922 United States Senate election in Mississippi was held on November 3, 1922. Incumbent Democratic U.S. Senator John Sharp Williams did not run for re-election to a third term in office.
In the Democratic primary to succeed Williams, U.S. Representative Hubert D. Stephens defeated former Senator James K. Vardaman, who had held Mississippi's other Senate seat for one term. The race required a run-off, as neither candidate achieved a majority in the August primary.
Stephens's victory in the September 5 run-off was tantamount to election; he faced on nominal opposition from the Republican and Socialist candidates in the November general election.
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