The Palazzo of Sangro di Casacalenda is the building that closes the southern side of the square of San Domenico Maggiore in the historic center of Naples. It was commissioned by Lucio di Sangro, the duke of Casacalenda and was built in the second half of the 1700s; the construction was started by Mario Gioffredo and finished by Luigi Vanvitelli.

Any building from the mere 1700s in the old city obviously was built on top of something else, and such is the case with the Palazzo Casacalenda. In order for the duke to build his home, he had to first remove what was left of a paleo-Christian church on the site, that of Santa Maria della Rotonda. Adjacent and somewhat earlier construction on the large San Domenico plague column in the center of the square also revealed the remnants of ancient walls of the city, of a city gate named Porta Puteolana [still the adjective for the modern town of Pozzuoli], and of a presumed temple to the Roman goddess, Vesta. In 1922, widening of via Mezzocannone, the road that comes up from the port area on the east end of Palazzo Casacalenda made it necessary to lop off an entire part of the building. (Before that, the square could not be accessed on that street by vehicular traffic.)

There are still frescoes within the Palazzo Casacalenda by Fedele Fischetti (1734-1789), a Neapolitan painter now regarded as somewhat of a minor artist, but whose works nevertheless adorn a number of sites in the area, including the Capodimonte Palace, the Royal Palace, and the Palace of Caserta. As is the case with many other large buildings in the historic center, it is difficult to stand back and look at this large classical facade and think that the building was at one time the residence of a single family, but it was. In the immediate area on the square, some of the buildings now house university spaces and some, such as Palazzo Casacalenda are given over to small shops at street level with the upper stories subdivided into private apartments.