Perkinsus (= Dermocystidium) marinus is a major cause of mortality in eastern oysters, Crassostrea virginica. Because initiation of infection and progression of disease are favored by high temperature and high salinity, we hypothesized that climatic cycles influence cycles of disease. Analyses of a 10-y time series of disease prevalence and intensity, chlorophyll a, suspended sediments, water temperature and salinity from a Louisiana site, using a wavelet technique, show a teleconnection between the El Niño-Southern Oscillation (ENSO) and oyster disease in the northern Gulf of Mexico. Salinity increases precede increased disease prevalence by several months. The changes in salinity that trigger changes in disease prevalence and intensity are strongly driven by ENSO events. Interannual variation is important in the initiation and intensification of disease, and salinity is the primary driving factor. The patterns in the environmental and disease time series suggest that epizootics can be initiated within 6 mo of a La Niña event, which produces increased water temperature and salinity. This relationship suggests an approach for predicting epizootics of P. marinus from climate models, which in turn can inform the management of oyster populations.