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Sheldon Cottrell, Roston Chase and Hayden Walsh each took three wickets as Kieron Pollard's side wrapped up the three-match series with a game to spare. Afghanistan have now lost 11 one-day internationals in a row.
Wicketkeeper Nicholas Pooran hit 67 off 50 balls to put backbone in the West Indies innings.
Openers Shai Hope (43) and Evin Lewis (54) put on 98 for the first wicket but the batsmen then lost their way until Pooran's man-of-the-match fireworks that included three sixes and seven fours.
Pooran admitted it had been a "critical situation" when he came in. He helped take the score from 156-4 to 242-8.
The Afghanistan innings was overshadowed by tens of thousands of black moths and flies that took over the floodlit Ekana Stadium in Lucknow.
Dark clouds of insects rose up every time the ball hit a boundary rope and several West Indies fielders wore masks. The moths caused problems for bowlers and batsmen, and Pollard twice spoke to the umpires about the nuisance.
"I've never played with so many flies around," said the West Indies captain after the game. "Health is very important, so something's got to be done about that." The third and final one-day game is on Monday but there are T20 games and a Test to follow - all in the same stadium.
Afghanistan lost Javed Ahmed in the opening over before Hazratullah Zazai (23) and Rahmat Shah (33) steadied in the innings. But easy wickets then fell before Najibullah Zadran (56) and Mohammad Nabi (32) put on 66 for the sixth wicket, hitting the insects for six.
No one else could keep up the pace after their departure. Captain Rashid Khan scored only two as the eighth man in.
"We recovered well, but couldn't finish it off," said Rashid. "The senior players did well, but we lost wickets in clusters." Walsh took three of the last four wickets to fall.
Pollard said it had been a great relief to finally win a one-day series for the first time since August 2014 when Bangladesh were the victims.
"I want to go back inside and celebrate with the guys. Winning is a habit and we need to enjoy ourselves but we will be playing to win again the day after tomorrow."
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