Following implementation of a routine childhood two-dose measles-mumps-rubella vaccination strategy, mumps disease levels dropped dramatically in the US and an elimination goal was set for 2010. However, a 2006 epidemic involved >5700 cases nationwide, with many reported among fully vaccinated college students. In an outbreak in two Iowa colleges, we investigated: (1) vaccination coverage using electronic records verified by provider records and (2) vaccine effectiveness assessed by comparison of dose-specific attack rates. Mumps was classified as typical (parotitis/orchitis) or atypical (parotid tenderness or submandibular/sublingual adenitis). Two-dose mumps vaccination coverage was 90% both for the student population (2128/2363) and case-students (97/108). Two-dose vaccine effectiveness was 76-88% with no significant difference for attack rates between one and two doses. Among two-dose vaccine recipients, 74% of the population (1482/2009) and 79% of the case-students (75/95) had received the second dose >10 years before. A large mumps outbreak occurred despite high two-dose vaccination coverage in a population most of whom had received the second dose >10 years before. Two-dose vaccine effectiveness was similar to previous one-dose estimates. Further studies are needed to examine the persistence of two-dose mumps vaccine-induced immunity and to determine whether US mumps elimination can be achieved with the current vaccination strategy.