The election pits 64-year-old Issoufou, a former mining engineer nicknamed "the Lion", against jailed opposition leader Hama Amadou, 66, known as "the Phoenix" for his ability to make political comebacks.
Polling stations opened at 8:00am (0700 GMT) and were to close at 7:00pm (1800 GMT), with 7.5 million people eligible to vote in an election which the opposition has vowed to boycott.
At Lamartine school in the Bani-Zoumbou district of the capital Niamey, the first voter cast his ballot at around 8:20am, an AFP correspondent said.
He said members of the electoral committee were present along with members of Issoufou's party but no-one representing the opposition, which did not send out any of its representatives.
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Amadou has been forced to campaign from behind bars after being detained on November 14 on baby-trafficking charges he says are bogus and aimed at keeping him out of the race.
Just days before the vote, he was evacuated from prison and flown to Paris for medical treatment, with the government saying he was suffering from an unspecified "chronic ailment."
"His health is improving and currently his condition is not life-threatening," said Luc Karsenty, a doctor at the American Hospital in western Paris.
The situation has created tensions in a country which has only had a multi-party democracy since 1990 and where three-quarters of the population live on less than USD 2 (1.80 euros) a day.