The Italian food chain has been confirmed as the fifth restaurant to open at Merepark's six-acre development behind Liverpool Central Station, Renshaw Street and Bold Street.
Prezzo will occupy 3,390 sq ft in the Lewis's building's new upper plaza, part of the £200m Central Village leisure and retail development, which is due to open in 2013.
The 135 seat outlet will be Prezzo's 170th restaurant in the UK and will sit adjacent to the six-screen Odeon cinema.
Earlier this year independent pan-Asian restaurant Cosmo also confirmed it will take space within the Grade 2-listed building.
The refurbishment and remodelling of the Lewis's building is currently underway with 80,000 sq ft of unused upper floor space being transformed to provide offices and a 129-bed Adagio hotel.
Other restaurants signed to scheme include The Handmade Burger Company, Chiquito and Frankie & Benny's.
Neal Hunter, associate director at Merepark, the developer of Central Village, said: "Central Village's proximity to Ropewalks and its link to Central Station provide operators with two very valuable assets – that of high footfall and wide appeal.
"This is evident in the success we've had bringing new national brands and independent operators into the city. Lettings to Prezzo and Cosmo, among others, give a very real sense of how Central Village will take shape and we're delighted with progress to date."
Savills advised Merepark on the letting.