Originally designed by architect James Renwick Jr., the 100-bed hospital opened in 1856, when the area was known as Blackwell's Island.

[8] The hospital is situated at the southern tip of the island, adjacent to Franklin D. Roosevelt Four Freedoms Park.

[3] When completed, it was a three-story, nine-bay U-shaped structure faced in granite veneer in a random ashlar pattern over load-bearing rubble masonry.

Despite the availability of the smallpox vaccine, New York City still had large outbreaks of the disease, due to the arrival of infected immigrants.

[9] Located on the isolated southern tip of the island in an attempt to quarantine patients, the hospital contained a large charity ward in addition to private rooms on the upper floors.

[9] In 1972, the hospital was added to the National Register of Historic Places, making it New York City's "only landmarked ruin.

[8] According to the AIA Guide to New York City, the remains of the Smallpox Hospital have the quality that architectural historian Paul Zucker, in his 1968 book Fascination of Decay, ascribed to ruins in general: "[A]n expression of an eerie romantic mood ... a palpable documentation of a period in the past ... something which recalls a specific concept of architectural space and proportion.