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It rises in the Front Range of the Rocky Mountains, in Larimer County, Colorado, in Rocky Mountain National Park on the eastern slope of Longs Peak, near the town of Estes Park. It descends steeply through the mountains in the spectacular 25-mile Big Thompson Canyon, emerging from the foothills near the city of Loveland.
It flows eastward across the plains into Weld County and joins the South Platte approximately five miles south of the city of Greeley. It receives the Little Thompson River approximately four miles upstream from its mouth.
On July 31, 1976, the Big Thompson Canyon was the site of devastating flash floods that swept the canyon in 1976, claming the lives of 145 people.