Background.Administration of M-M-R II (Measles, Mumps and Rubella Virus Vaccine, Live) and VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)] given concomitantly at separate injection sites during the same office visit could increase vaccine compliance by reducing the number of health care visits for immunizations. We compared the safety and immunogenicity of M-M-R II and VARIVAX given concomitantly at separate sites (Group A) with administration of the two vaccines 6 weeks apart (Group B) as well as the persistence of varicella antibody and the duration of protection afforded by varicella vaccine.Methods.A total of 603 healthy children, ages 12 months to 6 years, with no history of measles, mumps, rubella, varicella and zoster or vaccination against these diseases, were randomized to either Group A or B and were followed for clinical reactions and serologic responses to all four viral components. Children were enrolled from August through December, 1993. Subjects were followed for 5 years to evaluate persistence of varicella antibody and breakthrough varicella rates. We compared breakthrough rates to expected attack rates in unvaccinated children to produce estimates of vaccine efficacy.Results.Both vaccine regimens were generally well-tolerated. There were no significant differences between the groups in the rates of fever, injection site reactions or rashes after vaccination. Seroconversion rates and geometric mean titers for measles, mumps and rubella were not significantly different between groups. The varicella seroconversion rate and percentage with glycoprotein-based ELISA titers ≥5.0 units were similar between the two groups (99.5 and 92.5%vs.100 and 94.8% for Groups A and B, respectively), but the geometric mean titers were statistically significantly different (13.2 for Group A and 17.9 for Group B). Varicella antibody persistence rates were >98 to 100% during 6 years of follow-up in both groups. Compared with historical rates, varicella vaccine efficacy during 5 years was estimated to be 90.5% (95% confidence interval, 86.2%, 95.0%) and 88.9% (95% confidence interval, 83.7%, 93.7%) in Groups A and B, respectively.Conclusions.Administration of M-M-R II and VARIVAX concomitantly at separate injection sites or 6 weeks apart was generally well-tolerated and immunogenic in healthy children 12 months to 6 years of age. VARIVAX administered with M-M-R II induced persistent immunity and long-term protection against breakthrough varicella infection.