The tournament, which features the top 57 players on the European Tour, begins Thursday with Karlsson protecting a $372,100 advantage over two-time major winner Padraig Harrington.
Former champion Lee Westwood trails by $596,258 in third, ahead of Spanish challenger Miguel Angel Jimenez, who needs to make up an $864,770 deficit.
The 39-year-old Swede said he will treat this event like every other without the extra pressure.
If I start playing match play against Padraig and Westwood, I think were going to put ourselves in a lot of trouble, Karlsson said. I cant play on safety or anything like that. My focus is going to do my best this week and see on Sunday if its going to be enough. Its a tough task ahead.
Karlsson, who can become the first Swede to capture the year-end honor, finished in the top eight at every major except the PGA, where he was 20th. But perhaps the biggest reason he leads Harrington is that Karlsson has played 10 more tournaments this year.
Its not really a fair judgment of the season, said Karlsson, who won the Mercedes-Benz Championship and Alfred Dunhill Championship. But if you win it, youre not going to complain.
Harrington said he expects a stern test with the greens rolling quicker than usual. Strong winds are also expected on the 6,988-yard par-71 course, while heavy showers have been forecast for Friday.
Robert has performed more consistently in Europe than I have throughout the year, so consistency wise, and thats what an Order of Merit is, he probably deserves it ' but that doesnt mean he gets it, Harrington said. We have to wait until Sunday to sort that out.
Harrington, who is going for his second Order of Merit after edging Paul Casey in a dramatic finale two years ago, can be buoyed by one statistic: No champion has successfully defended his title.
With 2007 champion Justin Rose out of the Order of Merit picture, the contenders know the $904,589 prize is essential for their chances of winning at the Valderrama course, which is hosting the 21st edition of the European classic for the final time.
Ive got to go out there and try and win the tournament, and there are two bonuses with that: if I win the tournament, I win the Order of Merit. So thats whats in my mind for the week, said Harrington, who has shown tenacity at the last two editions with final round comebacks.
Former Volvo Masters champions Westwood (1997) and Jimenez (1999) face tougher tasks since catching Karlsson also depends on how the Swede performs. Both players need victories coupled with Karlsson low down the leaderboard to have any chance.
Sergio Garcia remains a contender for his first Volvo Masters trophy after three runner-up finishes at Valderrama. The 28-year-old Spaniard is coming off victory at the Castello Masters to snap a three-year European Tour drought.