The scrum-half, who was last season's breakthrough star in the competition, is brought in to replace the injured Edorado Gori.
Semenzato is one of seven changes made by coach Jacques Brunel to the line-up that was thrashed 42-10 by Ireland in their last outing.
Tobias Botes loses his place at number 10 to Australian-born fly-half Kris Burton after an erratic performance with the boot against Ireland.
Brunel has also brought experience into his back line with the inclusion of Racing Metro winger Mirco Bergamasco and Clermont centre Gonzalo Canale, who have 157 international caps between them.
Lock Cornelius van Zyl comes into the pack in one of three changes to the forwards, with Racing Metro prop Andrea Lo Cicero and flanker Simone Favaro also included..
Italy: Andrea Masi (Aironi); Luke McLean (Treviso), Gonzalo Canale (Clermont), Alberto Sgarbi (Treviso), Mirco Bergamasco (Racing Metro); Kris Burton (Treviso), Fabio Semenzato (Treviso); Sergio Parisse (Stade Francais, capt), Simone Favaro (Aironi), Alessandro Zanni (Treviso); Cornelius van Zyl (Treviso), Quintin Geldenhuys (Aironi); Lorenzo Cittadini (Treviso), Leonardo Ghiraldini (Treviso), Andrea Lo Cicero (Racing Metro/FRA)
Replacements: Tommaso D'Apice (Aironi), Fabio Staibano (Aironi), Marco Bortolami (Aironi), Robert Barbieri (Treviso), Tobias Botes (Treviso), Tommaso Benvenuti (Treviso), Giulio Toniolatti (Aironi)
Wales: L Halfpenny (Cardiff Blues); A Cuthbert (Cardiff Blues), J Davies (Scarlets), J Roberts (Cardiff Blues), G North (Scarlets); R Priestland (Scarlets), M Phillips (Bayonne); G Jenkins (Cardiff Blues, capt), M Rees (Scarlets), A Jones (Ospreys), A-W Jones (Ospreys), I Evans (Ospreys), D Lydiate (Newport Gwent Dragons), J Tipuric (Ospreys), T Faletau (Newport Gwent Dragons).
Replacements: K Owens (Scarlets), P James (Ospreys) L Charteris (Newport Gwent Dragons), R Jones (Ospreys), L Williams (Cardiff Blues), J Hook (Perpignan), S Williams (Scarlets)
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