A comparative clinical trial was conducted in 15- to 17-month-old healthy children to compare an investigational combination measles, mumps, rubella, varicella (MMRV) vaccine v standard measles, mumps, rubella vaccine followed 6 weeks later with the varicella (MMR + V) vaccine. Both the MMRV and MMR + V vaccine schedules stimulated virtually 100% seroconversion for all component viruses. Mean antibody titers were similar for each virus component in the two vaccine groups. Clinical reactivity postimmunization was also similar with 25% to 29% morbilliform rashes, 12% to 25% mild papulovesicular (varicella) rashes, and 12.5% to 18% temperature elevations above 38.3 degrees C (101 degrees F). Antibodies to measles, mumps, and rubella viruses were persistent at 1 year of follow-up in both groups. Varicella antibody was persistent in 8/10 originally seronegative MMRV vaccinees and 5/5 MMR + V vaccine recipients tested. One MMRV vaccine recipient had a household exposure to chickenpox during the year postvaccination that resulted in a subclinical boost in varicella antibody titer. Two children in the MMR + V vaccine group had close varicella exposures; mild varicella (20 lesions) developed in one. There were no known exposures to natural measles, mumps, or rubella. Three of four MMRV vaccinees with low titer antibody to varicella prior to immunization had greater than fourfold increases in antibodies after vaccination. The combination MMRV vaccine is an immunogenic, safe, and cost-effective approach to varicella immunization of healthy children. Continued work is needed to select the appropriate dose of varicella component, to assure higher persistence rate of varicella antibody.