We report that a calicivirus of oceanic origin, San Miguel sea lion virus serotype 5 (SMSV-5), is a human pathogen. This biotype was isolated originally from blisters on the flippers of northern fur seals (Callorhinus ursinus) and replicates readily in primate and human cell lines. It infects a phylogenetically diverse array of hosts (poikilotherms to primates) and induces type-specific neutralizing antibodies in exposed humans. Group antibody against a pooled antigen of SMSV-5 and two other serotypes was also observed in 18% of 300 blood donors from a population in the northwestern United States. The human calicivirus isolate designated SMSV-5 Homosapien-1 (SMSV-5 Hom-1) was recovered from a laboratory worker with systemic illness, including vesicular lesions on all four extremities. We believe this newly described human disease represents a paradigmatic shift in calicivirus disease recognition.