In heavy wind conditions, the 6-foot-5 Karlsson, who is playing his 20th season on the tour, shot a 2-under-par 70 for a 54-hole total of 11-under 205 at the famed Wentworth Club golf course.
"A four-shot lead is big, but it can go very quickly," Karlsson said. "It's important for me not to get caught up in what other players are doing and we have another 18 holes to play. This is the third week in a row I have been up there in a tournament, but I'm feeling good and looking forward to (Sunday)."
Overnight leader Paul McGinley (79) sank into a tie for fourth at 6-under 210.