Perkinsus marinus, a protozoan pathogen of the eastern oyster, Crassostrea virginica, infects oysters at high prevalences along the east coast of the United States. P. marinus was previously reported to be frequently apoptotic among the intestine epithelial cells in oysters collected from Long Island Sound. In this work, we study whether apoptotic activity of P. marinus cells is consistent with the distribution patterns of the parasite in the field in Long Island Sound and Chesapeake Bay. Prevalences and intensities of P. marinus infections were compared between Chesapeake Bay and Long Island Sound oysters during a 5-year period, from 1997 to 2001. In situ hybridization for apoptosis was performed on archived oyster histological tissues to detect differences in apoptotic indices (% of apoptotic P. marinus cells) between Chesapeake Bay and Long Island Sound oysters. Parasite apoptotic indices in Chesapeake Bay oysters were compared between different oyster habitat salinities. Two different P. marinus in vitro isolates, Chesapeake Bay isolate ATCC 50439 and Long Island Sound isolate ATCC 50508 were grown in cell cultures and exposed to different temperatures and salinities for 24 h. In situ hybridization assays for apoptosis were performed on cytospin preparations of the exposed cell cultures. During the five-year-period, the prevalences and intensities of P. marinus infections were significantly higher in Chesapeake Bay oysters. There was a significant increase in the prevalences and mean intensities of P. marinus infections in Chesapeake Bay oysters between the periods 1997–1998 and 1999–2001. This was largely because of increases in infection prevalences and mean intensities in Chesapeake Bay oysters from the low-salinity zone, where actual salinities and P. marinus associated disease in oysters were elevated by extended drought conditions during 1999–2001. Such a trend was not observed in Long Island Sound or in the higher-salinity zones of Chesapeake Bay. There was significantly more apoptosis of P. marinus in oysters from lower salinities than in those from higher salinities in Chesapeake Bay. Although temperature and salinity during a 24-h in vitro exposure affected apoptosis in both strains of P. marinus, the apoptosis dynamics significantly differed between the two P. marinus isolates with changes in salinity (11.6‰ to 37.8‰), but not temperatures (4°C to 35°C). The Chesapeake Bay isolate had an immediate decline in apoptosis at salinities above 11.6‰, and its apoptotic indices were low throughout the tested salinity range. The Long Island Sound isolate had high apoptosis at all salinities except 28‰, which is the approximate salinity where the Long Island Sound oysters are grown. We conclude that parasite apoptosis is an important factor regulating the distribution of P. marinus infections in the field. Our results suggest that Chesapeake Bay and Long Island Sound P. marinus strains may have evolved distinct genetic or phenotypic traits. The Long Island Sound strain reflects its adaptation to high-salinity oyster hosts, whereas the Chesapeake Bay strain possibly reflects adaptation to oyster hosts from low and variable estuarine salinities.