The British road race World Champion accelerated up the tough final climb to the Piazza del Campo in Siena to secure the victory in the opening race in the UCI's inaugural Women's WorldTour.
Armitstead – second last year behind Megan Guarnier – had been in a three-rider lead group with Katarzyna Niewiadoma (Rabo-Liv) and Emma Johansson (Wiggle-High5). The race is characterised by its sections of umade 'white roads' and the lead trio hit the final sector with a lead of around a minute on the chasing group.
Johansson was dropped near the base of the final cobbled ascent, leaving Armitstead and young Polish talent Niewiadoma to vie for the honours.
The more experienced Armitstead rounded the tight right-hand corner at the top of the final climb first, and continued to the line to take her second victory in two weekends after claiming Omloop Het Nieuwsblad a week ago.
"It's amazing to win the first UCI women's WorldTour event and this race is absolutely special," Armistead said after her victory.
"After winning in Belgium last week, thankfully I'm not affected by the curse of the rainbow jersey. I managed to honour it again today. We've shared the work in the last 10km with my two breakaway companions and I pulled away on the climb. It worked out really well."
Earlier in the race British cyclo-cross champion Nikki Harris (Boels-Dolmans) had put in a solo escape on the race's gravel sections, which suited her well. However, Harris was caught by Lucinda Brand (Rabo-Liv) after sector four and both were then caught by a 15-rider chase group.
Armitstead's victory means that she will be the first rider to lead the UCI Women's WorldTour.
The UCI Women's WorldTour continues with the Ronde Van Drenthe in the Netherlands on March 12.
Strade Bianche 2016: Siena to Siena, 121km
1. Lizzie Armitstead (GBr) Boels-Dolmans
2. Katarzyna Niewiadoma (Pol) Rabo-Liv at 3 secs
3. Emma Johansson (Swe) Wiggle-High5 at 13 secs
4. Elisa Longo Borghini (Ita) Wiggle-High5 at 1-04
5. Anna Van Der Breggen (Ned) Rabo-Liv at 1-07
6. Megan Guarnier (USA) Boels-Dolmans at same time
7. Annemiek Van Vleuten (Ned) Orica-AIS at 1-13
8. Claudia Lichtenberg (Ger) Lotto-Soudal at 1-17
9. Lauren Kitchen (Aus) Hitec at 1-21
10. Leah Kirchmann (Can) Giant-Alpecin at same time
14. Dani King (GBr) Wiggle-High5 at 1-29
23. Nikki Harris (GBr) Boels-Dolmans at 3-29
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