The 27-year-old, who won Thursday's giant slalom and also picked up a silver in the super-G on the same Roc de Fer slope, was first out of the starthut and clocked a leading 52.54 seconds.
Shiffrin looked completely at ease on the piste under sunny, warm conditions. The second leg is scheduled for 1230 GMT.
Switzerland's Wendy Holdener, a two-time Olympic slalom medallist, came in second, 0.19sec off Shiffrin's pace, with Canada's Laurence St-Germain third fastest (+0.61).
Only two other races got within one second of Shiffrin: Germany's Lena Duerr (+0.92) and Slovakia's reigning Olympic champion Petra Vlhova (+0.99).
Austrian hopes of a first gold at these champs lay with Katharina Liensberger, but the reigning world champion left herself with everything to do after finishing 14th, at 1.70sec.
Shiffrin, who previously won the world slalom title in 2013, 2015, 2017 and 2019, has firmly put behind her what she called the emotional rollercoaster she's been on after splitting with long-time coach Mike Day.
Just 24 hours after Day returned to the United States, Shiffrin won gold in Thursday's giant slalom for her seventh world title, joining an elite club of skiers comprising Toni Sailer, Marielle Goitschel, Anja Paerson and Marcel Hirscher.
Only Germany's Christl Cranz (12) has won more world titles, but she was skiing between 1934-39, when world champs were held every year and ski racing was yet to evolve to what it is nowadays.
Only Cranz (15) and Paerson (13) have as many world medals as Shiffrin (13).
Should Shiffrin triumph in the slalom, she would match Cranz as the only other skier, male or female, to have won at least five world titles in a specific event. Cranz won the women's combination five times.
Having also won slalom bronze in the 2021 worlds, Shiffrin would also become the first male or female to claim at least six world championships medals in a specific event, should she make the podium.
