Since 1991, 6 years after the recommendation of universal childhood vaccination against measles, mumps, and rubella (MMR triple vaccine), Switzerland is confronted with a large number of mumps cases affecting both vaccinated and unvaccinated children. Up to 80% of the children suffering from mumps between 1991 and 1995 had previously been vaccinated, the majority with the Rubini vaccine strain. On the basis of a case-control study including 102 patients and 92 controls from the same pediatric population, a study of the humoral immune-response following vaccination with the Rubini vaccine in 6 young adult volunteers, and two different genetic studies, we investigated the complex problem of large scale vaccine failure in Switzerland. We conclude that the recently reported large number of Swiss mumps cases was caused by at least four interacting factors: 1. A vaccine coverage of 90-95% at the age of 2 years is necessary to interrupt mumps wild virus circulation. The nationwide vaccine coverage in Switzerland of some 80% in 27-36 month-old children is too low. 2. Primary vaccine failures (absence of seroconversion or unprotective low levels of neutralizing antibodies), as well as secondary vaccine failures due to the rapid decline of antibodies to mumps virus in our volunteers and controls, seem to be frequent after vaccination with the Rubini strain. 3. Despite its reported Swiss origin, the Rubini strain does not belong to the mumps virus lineages recently circulating in this area but is closely related to American mumps virus strains. 4. Differences in protein structure between the vaccine strain and the circulating wild type strains, and in particular a different neutralization epitope in the hemagglutinin neuraminidase protein, may additionally contribute to the lack of protection in vaccinated individuals.