Oregon Route 99 technically starts at an interchange with Interstate 5 at exit 11, south of Ashland.

There it departs from the freeway, running parallel to I-5 as it passes through the cities of Ashland (as Main Street), Talent, Phoenix, and Medford.

OR 99 departs from I-5 several more times through the mountains of southern Oregon, only to rejoin again a short distance later.

Junctions are found in Gold Hill (2nd Ave), Grants Pass, between Myrtle Creek and Sutherlin (crossing I-5 in Roseburg), through Drain and Yoncalla, and Cottage Grove and Goshen.

West of downtown it heads north on an expressway alignment, which continues to Junction City.