Mackey was the first to reach the checkpoint at White Mountain, 123 kilometers (77 miles) from the finish line in Nome, arriving with 11 dogs at 8:43 p.m. Alaska Daylight Time on Monday.
His closest pursuers were Canada's Hans Gatt, 51, who just earned his fourth win in the 1,600-km (1,000 -mile Yukon Quest International Sled Dog Race and four-time Iditarod champion Jeff King, 54, both on the trail from the Elim checkpoint Monday night.
The front-runners could begin arriving in Nome as early as Tuesday afternoon. They must still take a mandatory eight-hour rest in White Mountain.
Mackey was runner-up in the Quest this year. He has won the race four consecutive times, including twice when he also won the Iditarod several weeks later.
King has said this is his last Iditarod.
The 57 remaining teams will continue up the Bering Sea coastline, sometimes traveling on the frozen ice in temperatures that were well below zero. This stretch is notorious for fierce winds that can create whiteout conditions in ground storms.
Meanwhile, a 3-year-old dog in rookie Justin Savidis' team has been found after being lost for nearly five days. The dog was reunited with Savidis late Sunday after being spotted near McGrath and lured in with a salmon carcass. The dog was lost between Nikolai and McGrath after apparently squirming free from his harness.
And though the race is nearing its conclusion for the leaders, anything can still happen.
In the 2008 race, Mackey and King were leading neck and neck for much of the route until they reached Elim. That's where Mackey pulled off a stunt that proved to be the turning point.
Mackey arrived at the checkpoint three minutes ahead of his rival, drank coffee and made a show of settling in for a nap. He told checkpoint volunteers to wake him in an hour and — with King snoring — sneaked out of the checkpoint 70 minutes ahead of his opponent.
This year's race is the first in Iditarod history where mushers were being tested for drugs and alcohol. Any positive results will be reviewed and could lead to penalties, such as disqualification.
Mackey has been open about using medical marijuana in past Iditarods. He said he is honoring the drug rule, which has existed in some form since 1984 but was never strictly enforced. Dogs have been tested for performance enhancers since 1994.