The Cleveland, Cincinnati, Chicago and St. Louis Railway, also known as the Big Four Railroad and commonly abbreviated CCC&StL, had main routes in Illinois, Indiana, and Ohio.

The railroad was formed on June 30, 1889 by the merger of the Cleveland, Columbus, Cincinnati and Indianapolis Railway, the Cincinnati, Indianapolis, St. Louis and Chicago Railway and the Indianapolis and St. Louis Railway.

The railroad once operated a terminal at Bellefontaine, Ohio which included the largest roundhouse in use at that time between New York City and St. Louis. The railroad was headquartered in Indianapolis, Indiana, at 105 S. Meridian Street. As of 2006 the building previously known as the Big Four Building is a Hampton Inn hotel.

By 1906, the Big Four was acquired by the New York Central Railroad. The Big Four's lines were incorporated into Penn Central in 1968 with the merger of New York Central and the Pennsylvania Railroad. Penn Central declared bankruptcy in 1970, and in 1976 many of Big Four's lines were included in the government-sponsored Conrail. Conrail closed the Bellefontaine terminal in 1983, and the roundhouse was dismantled. Conrail was privatized in 1987, and divided in 1999 between CSX and Norfolk Southern.