Keothavong also reached the semi-finals in Memphis last year
Anne Keothavong reached the Cellular South Cup semi-finals in Memphis but fellow Briton Elena Baltacha lost to top seed Maria Sharapova.
Keothavong beat Croatia's Karolina Sprem 6-4 6-3 to at least match her run to the last four of 12 months ago.
The British number three will next face Sweden's Sofia Arvidsson, who beat second seed Melanie Oudin 6-1 6-3.
British number one Baltacha went down 6-2 7-5 to Russia's three-time Grand Slam winner Sharapova.
Fifth seed Petra Kvitova of the Czech Republic defeated Estonian third seed Kaia Kanepi 1-6 6-3 7-6 (7-0) in the other quarter-final.
Keothavong, playing her first WTA main draw event after more than six months out with a knee injury, looked to be in for a tough match against world number 87 Sprem, a former top 20 player.
But the Londoner broke serve twice early in the opening set and never faced a break point as she forged ahead in the second, sealing victory on Sprem's serve after an hour and 11 minutes.
"This week has been better than I expected and I'm so pleased to have reached the semis of another WTA tournament, especially my first one back after time out through injury," Keothavong told her website.
"Every match here has been a bonus and I'm growing with confidence. My semi-final match against Sofia Arvidsson is a great opportunity for both of us.
"She's a good friend and we've played each other many times right from the junior days so I know what to expect. I'm looking forward to the challenge and really want to get through to a WTA final."
Arvidsson leads fellow 26-year-old Keothavong 4-3 in meetings on the WTA Tour, but the Briton won their last match on grass in Birmingham last summer.
Britain's Ross Hutchins and Australian Jordan Kerr are through to the doubles semi-finals after a 6-2 6-4 win over Michael Kohlmann and Jarkko Nieminen.
In the second round of the men's event, top seed Andy Roddick beat Yen-Hsun Lu 7-6 (7-2) 6-4 and there were also wins for Ivo Karlovic and Tomas Berdych.