Feline calicivirus (FCV), a member of the diverse family Caliciviridae, is a respiratory and oral pathogen of cats. Although conventional FCV vaccines are available, there are some safety and efficacy problems associated with their use. The potential of DNA vaccination against FCV infection was therefore explored. Four cats were inoculated intramuscularly with three 100 microg doses, 2 weeks apart, with a plasmid (pF9VAC) containing the mature capsid protein gene of FCV strain F9. Four control cats received the same plasmid lacking the FCV gene insert. All eight cats showed clinical signs following heterologous challenge with FCV strain LS027. However, rectal temperatures and general clinical sign scores were significantly lower in vaccinates compared to controls, and there was a marked difference in ulcer distribution between the two groups. Although no serological responses were detected in either group prior to challenge, post-challenge titres in the vaccinated group were generally higher. The results indicate that partial protection against a calicivirus is possible by DNA vaccination but that other approaches to enhance efficacy such as the use of cytokine genes or prime-boost protocols may also be required.