Epidemic keratoconjunctivitis (EKC) is a highly contagious, severe form of conjunctivitis. During 2008–2010, six unrelated EKC outbreaks associated with human adenovirus (HAdV) in four states were reported to CDC. In total, 411 EKC cases were identified in Florida, Illinois, Minnesota, and New Jersey. In each outbreak, health-care-associated transmission appeared to occur via ophthalmologic examination; however, community transmission was also documented. These outbreaks resulted in significant morbidity and cost resulting from the number of persons affected, duration of the outbreaks, and the temporary closure of a neonatal intensive-care unit (NICU) and several clinics. Clusters of EKC infections should be reported to the appropriate state or local health department. In settings where ophthalmologic care is provided, routine adherence to basic infection control measures and early implementation of enhanced outbreak control measures are essential to prevent HAdV transmission.