Fourth-seeded Fernando Gonzalez defeated Tommy Haas 7-5, 6-4 in his quarterfinal match and will play second-seeded and defending champion Juan Martin del Potro, who advanced after Robin Soderling withdrew before their match with a right elbow injury.
Playing in his first tournament since losing in the Wimbledon final, the fifth-ranked Roddick is two wins away from his fourth Washington title. He overcame the first two breaks of his serve in six career matches against the 6-foot-10 Karlovic.
"The way I kind of judge it, if at 30-all or at deuce point or in a breaker, if I'm able to step up and feel comfortable hitting my shots, that's a good sign," said Roddick, who on Thursday became the 36th player to reach 500 career match victories as a professional. "I've been able to do that so far this week."
Roddick entered the match with a 4-1 record against the Croatian, who leads the ATP Tour in aces with Roddick one spot behind. Their six previous sets had gone all the way to a tiebreaker, a trend that held in this match, even with both players breaking the other's serve twice.
After netting a forehand volley to go down 1-3 in the first, Roddick broke back to get it to 3-4. The action moved to that inevitable tiebreaker, which the top-seeded American took control of by winning the first three points.
"Being down an early break against Karlovic is a recipe for disaster," said Roddick, who has an ATP-best 29-6 record in tiebreakers this year. "I consider myself fortunate to get out it of it one time, much less two times."
Another set, another tiebreaker. Karlovic broke quickly at 1-0, leading Roddick to do his best Tiger Woods impression by driving a ball far out of the stadium.
His composure returned and after earning his second break, Roddick lost only five more points on his serve the rest of the way, while earning a mini-break to go up 4-3 in the tiebreaker.
As for why Roddick has gotten the better end of the tiebreakers between the two, including winning the last six, Karlovic said, "Luck, it's as simple as that."
Isner, who reached the final in 2007 as a qualifier before losing to Roddick, set up another chance by beating Berdych in their first head-to-head meeting.
The 80th-ranked American, who smashed 17 aces, served for the match at 5-4 and had three match points in the set before losing 12-10 in the tiebreaker. Isner rebounded to break Berdych twice in the final set, earning himself a semifinal round berth for the second time in three weeks.
Like Roddick, Gonzalez is playing in his first event since Wimbledon. Tied at 5-all in the first set, he angled a forehand past the charging Haas for the first break point of the match. He then had three forehand winners in his own service game to close out the set.
"Both of us played really good tennis in the beginning," said Gonzalez, who has been dealing with right knee tendinitis. "I only had one break point and I did it. That gave me a lot of confidence for the rest of the match."
Gonzalez broke serve to open the second set and again to go up 5-2 against a clearly frustrated Haas. A Wimbledon semifinalist this year, Haas broke back and then held his serve to get to 5-4. After losing the two next two games, the 11th-ranked Gonzalez rebounded and put away an overhead smash to win the match. He improved to 5-0 in quarterfinals this year.
"He made two mistakes in the first game [of the second set] and I took advantage," said Gonzalez, who reached the finals in Washington in 2003.
For his part, del Potro is hoping the day off following a lengthy third-round match will help him earn his first career victory against Gonzalez.
"I've lost to him three times in my career and I hope I can get my first win [Saturday]," said the sixth-ranked Argentine, who has picked up five tournament titles since their last head-to-head match in 2007.
"He's a different player now," Gonzalez said. "He's one of the new generation and he's had really good results the past year. But, it's better to have a positive record when you [next] meet."
Soderling, a finalist at the French Open, is expected to have an MRI exam on Friday.
"My elbow started to bother me two weeks ago and this morning it was really sore," the Swede said, adding that he hopes to play one or two tournaments before the U.S. Open.