MD Anderson's Houston Main Building (HMB) was opened by Prudential Insurance Co. in 1952 as its southwest regional office. At the time, the 20-story office building was Houston's tallest building outside downtown.

In 1974, MD Anderson purchased the 500,000-square-foot facility, which included 22.4 acres of land and a surface lot containing hundreds of parking spaces. The University of Texas officially named the building the Houston Main Building in 1980.

The acquisition of the building allowed executive and other administrative offices to move from the hospital to HMB to accommodate the expansion of clinical space. Over the years, MD Anderson updated and renovated some floors to support specific functions, and the expansive parking area was used for new construction.

The last employees moved out of HMB March 2010; the building was officially closed April 1, 2010. After its closure, contractors began the interior demolition and abatement of the building.

The master plan calls for the site to serve as the home of a new clinical building that would connect the Dan L. Duncan Building and the Lowry and Peggy Mays Clinic. Existing terraces on Floor 2 of these buildings will extend to the new facility, forming a courtyard above five floors of underground parking.

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