Parasitic, disease-causing pathogens can exert strong control over marine populations yet few long-term studies exist that describe these relationships. Understanding the connections to long-term large-scale processes relative to local short-term processes should facilitate better planning for disease impacts in the management of marine resources. We describe a 21-yr dataset of dermo disease (Perkinsus marinus) in eastern oysters (Crassostrea virginica) in Delaware Bay, USA. Analyses indicated (1) a strong positive association between disease and mortality that was non-linear and defined by thresholds, (2) a clear spatial gradient of increasing disease and mortality with increasing salinity, (3) an apparent 7-year cycle in which peaks were associated with strong positive anomalies of the North Atlantic Oscillation (NAO), (4) an inverse relationship with freshwater inflow, and (5) no obvious response to natural selection from persistent disease pressure. These data quantify the impact of environmental variables on the disease in a wild population and provide new insight into how disease interacts with host populations by linking disease patterns with larger climate controlling processes. Understanding these connections will facilitate prediction of and response to disease outbreaks.