When US 99 was the main Pacific Coast route between Canada and Mexico, it split in two for most of the length of the Willamette Valley. Between Portland and Junction City, there were two 99's. Highway 99E now exists only in pieces, having been covered over in places by Interstate 5 and generally obsolesced.

Highway 99W, however, still is a major route on the west side of the valley. Going southwest from Portland, it passes through Tigard and Newberg before turning south close to McMinnville.

Passing some 20 miles west of Salem, it goes through Monmouth and Corvallis before turning southeast at Monroe and converging with Highway 99E at Junction City.

Highway 99W crosses much of Oregon's Wine Regions of Oregon, particularly in Yamhill County.