This line was founded by the Bellefountaine ("Bee Line") Railway in 1868 to compete with William Riley McKeen’s Terre Haute & Indianapolis Railroad. The line eventually entered into an agreement to use the St. Louis, Alton & Terre Haute tracks west of Terre Haute. In the 1870s, it built a passenger depot on the north side of Sixth and Tippecanoe streets and an elaborate freight depot two blocks west. Ultimately, the Indianapolis & St. Louis and its affiliates were absorbed by the Cleveland, Cincinnati, Chicago & St. Louis Railroad, known as "The Big Four."

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