Nadal trailed 4-2 in the opener but recovered, breaking twice to take it.
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The 11-time tournament champion looked ready to roll to a quick victory after dominating the first set, but Nishikori responded with some fine net play to level it at 1-1.
Defending champion Rafa Nadal progressed to the quarter-finals of the Barcelona Open with a straight sets win over his friend and compatriot David Ferrer on Thursday.
Nadal, who won both Monte Carlo and Barcelona for an 11th time, will also reclaim the coveted world No 1 ranking from Roger Federer when the latest set of rankings are released on Monday
The News Agency of Nigeria reports that Tsitsipas, 19, is the second-youngest player in the ATP top 100.
Nadal also extended his winning streak on clay to 44 consecutive sets with a comfortable 6-4 6-0 win over the Belgian on Saturday
World number one Nadal, chasing an 11th title at the tournament, a week after claiming the Monte Carlo Masters for an 11th time, will next face Slovakia’s Martin Klizan
Rafa Nadal, who has won the tournament 10 times, also reached the last eight after dispatching compatriot Guillermo Garcia-Lopez 6-1 6-3 and claiming a record-extending 40th consecutive set on clay.
The former world number one is trying to find some form ahead of next month’s French Open, but the 30-year-old has been dealt a further blow in his preparations for Roland Garros
The former British number two failed the test at the Barcelona Open in April and announced the news at an emotional press conference in June