The 34-year-old beat compatriot Sofia Goggia by 0.01 of a second to take the lead in the super-G standings from Switzerland's Lara Gut-Behrami, now five points behind with 100 remaining to be won.
Goggia is out of contention, 104 points behind Brignone.
In the overall standings, Brignone is 382 clear of sole rival Gut-Behrami with a maximum 400 still up for grabs from four races at the World Cup finals in Sun Valley, Idaho, from March 20th-27th.
Brignone and Gut-Behrami, who was fourth-equal with compatriot Corinne Suter in Friday's race, do not normally compete in slalom, one of the four remaining disciplines.
The victory was Brignone's 10th of a season in which she has also won world championship gold in giant slalom, and 37th of her career.
The Italian could end the campaign with four of the five crystal globes since she leads the downhill standings and is only 20 points behind New Zealand's Alice Robinson in giant slalom.
Brignone won the overall World Cup in 2020 after American defending champion Mikaela Shiffrin took time out following the death of her father in February of that year.
"This is an amazing day. Winning in front of my people is something that I really wanted this year. It was one of my biggest dreams, to win here in La Thuile," said Brignone, who started with bib number six.
"I couldn't finish my career without it," added the Italian, who has next year's Milan-Cortina Olympics on home snow also to look forward to.
France's Romane Miradoli completed Friday's podium after being the first skier to start, with 40-year-old Lindsey Vonn the highest-placed American in 13th and 0.70 off the pace.
Thursday's super-G winner Emma Aicher of Germany failed to finish, along with Robinson.