After three draws on Monday, the 54-year-old former world champion -- who dominated the game from 1985 to 2000 -- had hoped to play "more aggressive" chess on day two of the Rapid and Blitz tournament in St Louis.
But after drawing his first game yesterday with Armenian world number four Levon Aronian, a contest that featured some gutsy moves from Kasparov and a few trademark death stares, he could not hold on against Nepomniachtchi.
"I haven't played serious chess in 12 years, & haven't missed as many opportunities as I did today in 15! Hoping to steady the ship tomorrow!" tweeted Kasparov at the end of the day.
"I was too democratic today. I made quite a few good moves, but spread them evenly among all three games instead of concentrating them!"
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After his loss Kasparov's fans, all hoping to see the brilliance that characterized his long career, said they were disappointed but still hopeful.
Kasparov, who left the game in order to pursue a career in politics, will need some wins if he wants to move up in the tournament rankings -- he started Tuesday in 7th position out of 10.
Victories would give his comeback some symbolic power -- Kasparov would be seen as passing the torch to a new generation, albeit a generation still spellbound by his talent.
But those more youthful players seem determined to knock Kasparov from his pedestal.
American grandmaster Robert Hess had predicted a "tough day," saying that "every opponent is extremely strong, so Garry will certainly need to bring his A game if he is going to try to score some victories."
Though the winner's purse in St Louis is a not-too-shabby $150,000, Kasparov said he would donate any winnings to promote chess in Africa.