In a moving conclusion on Court Two, Del Potro sat next to a sobbing Almagro, offering him water while patting the head of the inconsolable 31-year-old.
"Today I think I got lucky, because I don't feel good enough with my body", he added.
Czech second seed Karolina Pliskova is into the third round of the women's singles for the first time after a 6-2 4-6 6-3 win over Ekaterina Alexandrova.
When Spanish tennis player Nicolás Almagro broke down after a recurring knee injury again forced him to quit a major tournament mid-match, his opponent stepped up.
World number one Sir Andy Murray recovered from a set down to reach the third round of the French Open with victory over Martin Kližan at Roland Garros.
But, assuming he is close to fully fit, Del Potro will present a serious test of Murray's Roland Garros ambitions with the pair having played in two classic matches previous year - the Rio Olympic final and a marathon Davis Cup five-setter - both stand-out memories.
World number 50 Klizan has already hit the headlines in Paris by being accused of faking an injury in his opener against French wildcard Laurent Lokoli.
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Having arrived in Paris short of wins and confidence, Murray was hoping the best-of-five-set format and relatively kind draw would allow him to play himself into form.
Almagro fell to the ground, audibly crying, as Del Potro crossed over the net and crouched beside him trying to console him. In Miami I think he lost to Roger [Federer].
The three other Top 10 seeds in action Thursday all eased through in straight sets as No. 3 Stan Wawrinka caged Alexandr "The Dog" Dolgopolov 6-4, 7-6 (5), 7-5, No. 7 Marin Cilic beat Russian Konstantin Kravchuk 6-3, 6-2, 6-2, and No. 8 Kei Nishikori held off France's Jeremy Chardy 6-3, 6-0, 7-6 (5).
Last year's runner-up Murray entered the third round with a hard-fought 6-7 (3/7), 6-2, 6-2, 7-6 (7/3) win over Martin Klizan of Slovakia. I said to him, "Try to be calm". "What I like, especially when I play in Grand Slam tournaments, is that momentum where match after match you not only play consistently but you play better and better". Make Del Potro hit as many balls as possible, and he'll eventually wear down and throw in some unforced errors that top tier players pounce on. "It was tough" said Del Potro.
British number two Kyle Edmund also progressed after beating Renzo Olivo 7-5 6-3 6-1. He'll go through patches in the match where he's playing some unbelievable stuff and then he drops off a little bit and plays some unusual shots which may appear like he's not interested but that's how he plays the game.
Murray produced an encouraging four-set win over Andrey Kuznetsov in round one, but the early signs were not good against the risky Slovak.
"I just do what my heart feels".
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