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.
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 the chic western Paris suburb of Neuilly.
More From This Section
The situation has created a tense atmosphere in the country where three-quarters of the population live on less than USD 2 a day.
Niger's history is peppered with military coups and it has only had a multi-party democracy since 1990.
The run-up to the first-round vote was marred by violence between supporters of the rival camps, the arrest of several leading political personalities and the government's announcement that it had foiled a coup bid.
During the campaign, Issoufou, who took office in 2011, repeatedly pledged to bring prosperity to this desolate but uranium-rich country and prevent further jihadist attacks in its vast remote northern deserts and from Nigeria's Boko Haram Islamists to the south.
Just three days before the vote, Niger suffered two jihadist attacks -- one in the west claimed by Al-Qaeda's north African affiliate which killed three gendarmes and another by Boko Haram in which a senior army officer died.
His supporters accuse Issoufou's regime of bad governance, saying it has failed to eradicate poverty in the country.
But a clear-cut victory appears assured for Issoufou, who missed winning an absolute majority in the first round by just 75,000 votes.