A 5-day-old, mother-raised, Amur tiger cub (Panthera tigris altaica) presented with tongue ulcerations. Identical lesions appeared and progressed to sloughing of the tongue in the three littermates of this cub the following day. The lesions progressed in all cubs to include sloughing of the carpal, tarsal, metacarpal, and metatarsal foot pad epithelium. Oral ulcerations were also noted in adult African lions (Panthera leo) and Amur tigers (Panthera tigris altaica), but not in two adult snow leopards (Panthera uncia) housed in the same building. All adult cats had been previously vaccinated for common feline diseases including feline calicivirus (FCV). Detection of FCV RNA in oral secretions by a real-time reverse transcription polymerase chain reaction assay (RRT-PCR) confirmed FCV infection in the tiger cubs and one lion. A male lion and a male tiger cub died during the disease outbreak. RRT-PCR confirmed FCV in multiple tissues in both of these animals. A stray cat live-trapped outside the feline building during the epidemic was found to be positive for FCV by virus isolation and was thought to be the source of infection.