That was enough to defeat Tina Weirather by nearly a second, while Vonn's compatriot Jacqueline Wiles completed the podium (+0.98s).
"I'm getting more and more comfortable and from here on out it's just about the timing and hitting my switches in the right spot", said Shiffrin, who claimed the first downhill victory of her career in Lake Louise in November. The overall World Cup leader now by almost 1,000 points, Shiffrin finished seventh on Saturday.
She got off to a slow start, trailing in 13th in the first downhill training run in the Italian Dolomites this week, but moved up to fifth in the second training run before her third in the race.
The most successful USA female Alpine skier with nine medals - four Olympic and five at world championships - has struggled with hip pain throughout her career and formally retired in the Italian resort of Cortina d'Ampezzo on Friday.
Vonn will go for her 80th career win Sunday in a super-G at Cortina, where she's now won six downhill and six super-G races. Then she casually made her way down the Olympia delle Tofane course as the Wonder Woman theme song played on the public address system.
"It was good, clean skiing today".
"This is just the moment I was planning on going into the Olympics", said a delighted Vonn with the Winter Games closing in fast on February 9.
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Wiles was skiing just off Vonn's pace at the top intervals but almost overcooked a turn after catching a rut. "A little scary at the bottom, but I kept is rolling and it came together".
The podium was instead completed by Vonn's compatriot Jackie Wiles who became the fifth United States female alpine skier to qualify for the Olympic Games.
But she said her mind was more on Pyeongchang. "She's a great friend, and role model, and I'm super thrilled to be on the podium with her". Vonn and Mancuso are the same age, raced against each other as juniors and joined the U.S. Ski Team at the same time.
The 22-year-old - competing for the first time in the downhill in Cortina - finished on the podium Friday behind Italy's Sofia Goggia and fellow American Vonn, who paid for a mistake in her run.
It was a vast improvement from the ninth and 27th places that Vonn recorded in Bad Kleinkirchheim in a super-G and downhill, respectively, last weekend. "It's lovely. It's hard not to be happy", said Vonn, who is wearing a Captain America themed racing suit this weekend with a big white star on her chest. "I don't think that I was ever looked at as the favorite and I always managed to do the best for me and ski the best for me and sometimes that brought gold medals, which was incredible".
"For me good to get a good result to build my confidence and get a good result going into the Olympics", she continued.