Transforming the concrete and glass mission into an embassy will be a central part of historic negotiations between US and Cuban officials this week aimed at restoring diplomatic relations.
Guarded by stone-faced Cuban police officers, the building that was built in 1953 lies along the famous Malecon seawall, a favorite meeting spot for locals and tourists alike.
Cars are forbidden to park in front of it and police chide pedestrians who want to walk along the facility.
Since then, the mission and its 360 staff members -- most of them Cuban nationals -- officially mostly handle consular operations and work to promote human rights.
Now the United States wants to turn the building back into an embassy with an ambassador, with more freedom of movement within Cuba for its American staff.
This will be negotiated on Thursday between senior US State Department official Roberta Jacobson and Cuban foreign ministry official Josefina Vidal.
For years, the Castro regime has denounced the mission as the tip of the spear of US conspiracies against Cuba.
In 1980, the mission angered the government by offering protection to around 400 asylum seekers during the Mariel boatpeople crisis, during which 125,000 Cubans fled to the United States.
Huge anti-American demonstrations were held with as many as five million, half the island's population, taking part.
But it was in the new millennium that tensions around the interests section reached a fever pitch.
Across the main entrance, the Cuban government built a vast esplanade with an "anti-imperialist platform" for anti-US rallies.
The venue was built in 2000 during the Elian Gonzalez custody saga -- after a young boy was plucked from an inner tube by the US Coast Guard after his mother died while crossing the Florida Strait, and his Cuban father demanded his return.