Beginning Thursday, more than a foot of snow is likely in the Bitterroots, Wasatch, Colorado High Country, and the Sierra of California.
Lighter snowfall totals are expected in the Cascades and Siskiyous.
The snow will spread into the Plains and Great Lakes starting early Thursday and continue through Friday.
On Saturday, another wave of light to moderate snow, sleet and freezing rain is expected to spread from the central Plains to the mid-Mississippi Valley, Ohio Valley, Great Lakes, western, central and Upstate New York, and parts of New England.
This second wave will produce challenging winter driving conditions from Kansas and Missouri to Upstate New York and northern New England.
Total snowfall accumulations could top six inches in a broad swath from Nebraska and Kansas to Upstate New York by Saturday night.