The 26-year-old Edinburgh star is joined in the team by clubmate Geoff Cross who is promoted from the bench as Euan Murray's religious beliefs prevent him from playing on Sundays.
Scotland boss Andy Robinson makes a further two changes to his replacements following the 13-6 defeat to England, with Glasgow full back Stuart Hogg and Duncan Weir winning call ups.
Weir takes the spot vacated by Laidlaw, while 19-year-old Hogg is included after a stunning solo score in the A side's 35-0 win over England Saxons. Both men are uncapped at senior level.
"Congratulations to Greig on his first start," said Robinson, after rewarding Laidlaw for a fine display as a second-half substitute against the English and an even finer Heineken Cup campaign with Edinburgh.
"He's a gifted footballer who is acclimatising very well to the differing demands of the stand-off position from having spent most of his career at scrum-half.
"Having lost last weekend, I believe the time is right to move on and look to develop our emerging talent at stand-off.
"I've always stressed the importance of the A team and the part that both Duncan Weir and Stuart Hogg played in the game at Netherdale last week is another reason for my continued excitement and belief in Scottish rugby."
Scotland (v Wales, Millennium Stadium, Sunday, 3pm)
15 Rory Lamont (Glasgow Warriors)
14 Lee Jones (Edinburgh Rugby)
13 Nick De Luca (Edinburgh Rugby)
12 Sean Lamont (Scarlets)
11 Max Evans (Castres)
10 Greig Laidlaw (Edinburgh Rugby)
9 Chris Cusiter (Glasgow Warriors)
1 Allan Jacobsen (Edinburgh Rugby)
2 Ross Ford (Edinburgh Rugby) captain
3 Geoff Cross (Edinburgh Rugby)
4 Richie Gray (Glasgow Warriors)
5 Jim Hamilton (Gloucester)
6 Alasdair Strokosch (Gloucester)
7 Ross Rennie (Edinburgh Rugby)
8 David Denton (Edinburgh Rugby)
16 Scott Lawson (Gloucester)
17 Ed Kalman (Glasgow Warriors)
18 Alastair Kellock (Glasgow Warriors)
19 John Barclay (Glasgow Warriors)
20 Mike Blair (Edinburgh Rugby)
21 Duncan Weir (Glasgow Warriors)
22 Stuart Hogg (Glasgow Warriors
NB Bold denotes Lion