We conducted a 36-mo study to determine the effects of environmental variables and proximity to infected resident oysters on Perkinsus marinus infection acquisition and progression in specific-pathogen-free (SPF) juvenile oysters in the Patuxent River, MD, a mesohaline tributary of Chesapeake Bay. Multiple deployments of experimental SPF oysters were made at four sites along the river's salinity gradient, with three sites adjacent to infected resident oyster populations and one site isolated by at least 5 km from known oyster populations. Experimental cohorts were analyzed for dermo disease at deployment (time 0), approximately 2 and 4 wk, and at subsequent monthly intervals, using quantitative whole-body-burden alternative Ray's fluid thioglycollate medium (ARFTM) assays. Some oysters in some experimental groups acquired P. marinus infections as early as 10 d after placement in dermo disease-enzootic waters, and infections were detected in all groups by 62 d postdeployment. In several cohorts, first infections were simultaneously detected among >62% of experimental oysters, reflecting epizootics within 8 wk of their exposures to local infection pressures. Threshold values of 12‰ for salinity and 24°C for water temperature influenced infection acquisition rates. Isolation of SPF juvenile oysters from known populations of infected resident oysters did not prevent or delay acquisition of dermo disease during drought conditions. Once initial infections occurred, infection prevalences and mean intensities increased over time in all experimental oyster cohorts.