An attenuated respiratory disease vaccine against feline viral rhinotracheitis (FVR) and feline calicivirus (FCV) disease was evaluated for safety and efficacy in specific-pathogen-free cats. Twenty cats were vaccinated twice intramuscularly, with 28 days between vaccinations. Ten unvaccinated cats were used as contact controls. Adverse effects were not noticed after vaccination, and the vaccinal virus did not spread to contact controls. Arithmetical mean serum-neutralizing titers against vaccinal FCV strain F9 and challenge FCV strain 255 were 1:13 and 1:15 at 28 days after the 1st inoculation. These titers increased to 1:45 and 1:196 after the 2nd inoculation. After challenge exposure of vaccinated cats to virulent FCV 255 virus, mean titers increased to 1:129 and 1:865, respectively for F9 and 255 viruses. The F9 postchallenge mean titer for vaccinated cats was 21.5 times higher than that for the 8 contact controls that survived challenge exposure. The arithmetical mean serum neutralizing titer for FVR was low (1:2) after the 1st vaccination, but increased to 1:35 after the 2nd vaccination. Challenge exposure to virulent FVR virus resulted in a marked anamnestic immune response (mean titer of 1:207, compared with 1:12 for contact controls). In general, vaccinated cats remained alert and healthy after challenge exposure with FCV-255, whereas unvaccinated contact control cats developed definite signs of FCV disease, including central nervous system (CNS) depression (6 of 10) and dyspnea indicative of pneumonia (5 of 10). Two controls died of severe pneumonia. A mild fibrile response was detected in 28% of vaccinated cats, compared with a more severe febrile response in 78% of control cats. Some vaccinated cats developed minute lingual ulcers that did not appear to be detrimental to the health of the cat. After FVR challenge exposure, vaccinated cats were free of serious clinical signs. Five of 18 vaccinated cats had mild signs of FVR, including an occasional sneeze, low temperature, and mild serous lacrimation for 1 or 2 days. Contact controls developed definite clinical signs of FVR. The combined FVR-FCV vaccine appears to be safe and reasonably efficacious. Vaccination against FCV disease and FVR should be part of the routine feline immunization program.