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The success of the measles, mumps, and rubella 2-dose vaccination program led public health officials in 1998 to set a goal to eliminate endemic transmission of mumps virus by 2010 in the United States. The large outbreak of mumps in the spring of 2006 has led public health officials to re-evaluate this goal and to recognize that the transmission and epidemiology of mumps in highly vaccinated populations may be different than anticipated. During 2006, a total of 6584 confirmed and probable cases of mumps were reported to the Centers for Disease Control and Prevention and most of these, 5865, occurred between January 1 and July 31. The peak of the outbreak was in April and seemed to be focused on college campuses in 9 midwestern states with Iowa having the highest attack rate. College campuses with mumps outbreaks included ones with 77% to 97% of students having had 2 doses of a mumps vaccine. Diagnosing mumps proved to be problematic in vaccinated persons (ie, laboratory tests seemed to be insensitive and some apparent mumps cases had mild nonclassic illness). The outbreak demonstrated that mumps can sometimes transmit efficiently in highly vaccinated populations and the clinical and laboratory diagnosis of mumps in vaccinated persons is more difficult than in naive persons. The reason for this mumps outbreak is not clear but probably results from multiple factors contributing to an overall increase in susceptibility and/or transmission.