De Luca, who will be giving his thoughts on the league season to this site in the run up to the end of season Play-Offs, starts at outside centre for the Calcutta Cup tie at Murrayfield.
The 26-year-old is the only personnel change to the Scotland XV that lost to Italy in Rome last time out.
De Luca hasn't started for his country for 16 months since the win over Canada at Pittodrie in November 2008.
He wins his 16th cap, having impressed for Edinburgh in their convincing win over previous Magners League leaders the Ospreys last weekend.
Glasgow centre Max Evans switches to the left wing, with Ulster's Simon Danielli dropping to the bench.
There is disappointment for Edinburgh skipper Mike Blair as the British & Irish Lions tourist misses out through injury, as do Gloucester duo Alasdair Strokosch and Alasdair Dickinson.
Blair was concussed during the 33-17 win over the Ospreys and will therefore play no part at his home ground, but clubmates Geoff Cross and Alan MacDonald do feature on the bench having not been involved against the Italians.
Glasgow's Chris Cusiter and John Barclay have recovered from a virus and a knee injury respectively to take their places in the starting line up.
"The team has played some good rugby and we have been creating chances. We just need to take that next step and finish off a game," said Scotland head coach Andy Robinson, a former coach of the England national side and an ex-England international.
Robinson has selected 13 Magners League players in his chosen XV, plus another five among his seven replacements.
Glasgow contribute the most players with eight; Edinburgh are next in line with seven; while Leinster, the Scarlets and Ulster provide one apiece.
Scotland
15 H Southwell (Stade Francais)
14 S Lamont (Scarlets)
13 N De Luca (Edinburgh)
12 G Morrison (Glasgow)
11 M Evans (Glasgow)
10 D Parks (Glasgow)
9 C Cusiter (Glasgow, captain)
1 A Jacobsen (Edinburgh)
2 R Ford (Edinburgh)
3 E Murray (Northampton)
4 J Hamilton (Edinburgh)
5 A Kellock (Glasgow)
6 K Brown (Glasgow)
7 J Barclay (Glasgow)
8 J Beattie (Glasgow)
Replacements
16 S Lawson (Gloucester)
17 G Cross (Edinburgh)
18 N Hines (Leinster)
19 A MacDonald (Edinburgh)
20 R Lawson (Gloucester)
21 P Godman (Edinburgh)
22 S Danielli (Ulster)
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