The National Oceanic and Atmospheric Administration (NOAA) Status and Trends Mussel Watch Program sampled the largest oysters in nearly every major US coastal lagoon and estuary in the Gulf of Mexico once during the winter from 1986 to 2010. This contribution examines trends in the principal oyster disease in the Gulf of Mexico, Dermo, caused by Perkinsus marinus, and some related population dynamic characteristics for its host, Crassostrea virginica. During the 1986–2000 period, P. marinus prevalence and infection intensity and oyster population dynamics followed the El Niño-Southern Oscillation (ENSO) cycle, responding to variations in salinity caused by variations in rainfall and freshwater inflow. The ENSO signal in the oyster population effectively ceased circa 2002. Beginning around this time, wintertime P. marinus prevalence and weighted prevalence began a decadal decline, as did the length of the largest oysters and the fraction of these largest animals that were female. The trends in Dermo disease, oyster length, and oyster sex ratio are all consistent with the following hypothesis: increasing temperature during the 2000s resulted in an increase in P. marinus infection intensity sufficient to increase the mortality rate in late summer and fall in the larger animals. This simultaneously reduced Dermo prevalence and infection intensity in the winter at the time of sampling and also resulted in the decline in the length of the largest animals targeted by Mussel Watch. Coincident with the decline in length is the expected decline in the fraction female, such that the percent female in the largest animals dropped to ≤50 % throughout much of the Gulf of Mexico. The decline in length leading to fewer large animals reproducing and the loss of females are predicted to have reduced oyster population reproductive capacity substantially during the 2000s. The early 60 % of the Mussel Watch time series took place during a period of negative Atlantic Multidecadal Oscillation (AMO) indices. The AMO moved into positive territory circa 2000. A positive AMO index is consistent with observed warmer water temperatures, and increased water temperature is consistent with an increase in Dermo-induced mortality.