A calicivirus was isolated from 3 dairy calves in a herd with persistent calf respiratory tract problems. This virus, named Tillamook calicivirus, was not neutralized by 18 different calicivirus-typing serums available. The agent caused only minimal lesions in 2 experimentally exposed calves, but did establish a persistent infection with virus shedding for 45 days, after which time the experiment was terminated. Experimentally exposed swine developed clinical vesicular lesions. The possible origins, disease potential, and relationships to the exotic animal disease agent, vesicular exanthema of swine are discussed for this first calicivirus isolate of bovine origin.