"It definitely feels good any time you can avenge a loss," Blake said. "He's an excellent player, and 18 years old, he's got a huge learning curve and will continue to get better."
Next up for Blake is Texan Ryan Harrison, who on Monday became only the 11th player in the Open Era to win a main-draw match at 15. The two Americans play Thursday night.
"I feel like I'm back in a junior tournament," Blake said. "It's amazing that this kid is 15 years old and won a round in a tour event. I know he's going to come out tomorrow with nothing to lose. That's always dangerous."
Blake's brother, Thomas Blake, watched Harrison win his first-round match.
"I don't know a whole lot about him," James Blake said. "I'm sure not many people have a scouting report on him 'cause he's so new to the tour."
Blake, the world's No. 8 player, closed out Nishikori with an ace.
Service breaks riddled the second set. Nishikori, 18 and ranked No. 116 in the world, broke Blake in the second game. The American returned the favor in the next game, and the two traded breaks in their next service games to give Nishikori, a wild- card entry, a 3-2 lead.
Blake then held at love to level it at 3-3 before breaking the teen -- Nishikori double-faulted to drop his serve -- to take the lead for good.
The top seed converted on four of 11 break points, while Nishikori got only two of four.
Nishikori said Blake played more aggressively than in their Florida match.
"He was hitting the ball harder," he said. "He was stepping inside the court."
In the evening's last match, third-seeded Mardy Fish beat American countryman Hugo Armando 6-3, 6-2.
Earlier in the day, Nicolas Massu rallied to beat fourth-seeded Sam Querrey 5-7, 6-4, 6-4. The Chilean and Querrey traded breaks early in the third set but Massu, who is ranked No. 108, broke the American in the ninth game to serve for the match at 5-4. Massu won four straight points to claim the win.
"I think that after the first set I was not satisfied," Massu said. "I was fighting, fighting, and I won the match. I think that I didn't play my best tennis today but tomorrow is different."
He is scheduled to play Brazilian Marcos Daniel, who also advanced with a 6-3, 6-4 victory over Serbian Viktor Troicki, on Thursday.
Querrey, ranked No. 50, hit a return of serve long to end the match.
"It could have gone either way there," said Querrey, who got only 44 percent of his first serves in. "I didn't serve my best. Other than that it was pretty good. I'm not too disappointed."
In other matches Wednesday, No. 8 seed Oscar Hernandez of Spain beat American Donald Young 6-4 ,6-4 to advance to the quarterfinals.
In first-round play, Paul Capdeville of Chile advance, beating Argentine Diego Hartfield 6-0, 6-4, and Peter Luczak of Australian edged Harel Levy of Israel 6-4, 6-4.