Specific-pathogen-free (SPF) oysters (Crassostrea virginica) were set on shell and deployed on three oyster bars along a salinity gradient in the Patuxent River, MD, to determine growth, time to initial infection by Perkinsus marinus (causative agent for dermo disease), and subsequent mortalities. Initial deployment was in September 2000, during the second year of a 4-y drought. The salinity gradient experienced by these oysters during the drought was 4‰ to 6‰ above normal and provided ideal conditions for proliferation and dissemination of P. marinus. Oysters grew well during the first year, but mortalities rose rapidly during the second year, and reached 97% to 98% at all sites by the end of the second year. Although mean P. marinus body burdens reached levels of 2.3 × 107 cells·g−1 oyster tissue, MSX disease was also detected at both the lower and midriver sites in 2002, and was probably responsible for some mortalities at those sites. Due to extensive mortalities of the first deployment, we began to monitor a second group of oysters that had been deployed in May 2002. These oysters experienced a first year of extreme drought, followed by a freshet year during 2003. By the end of the study in November 2003, the overall growth of these oysters (64 mm) was similar to that observed for the first deployment (63 mm), but mortalities were much lower (maximum 58% at the downriver site and 0% at the upriver site). Perkinsus marinus infections in feral oysters, which were the probable source of infectious cells for SPF oysters, showed differences among sites before the drought and during the 2003 freshet year, but no site differences were detected during the 2000–02 drought years. Condition Indices (CI) differed between harvest and spawning seasons, and was greater at the upriver site than at the others during the drought. No site differences were detected for CI during the freshet. Results of this study showed that use of SPF juvenile oysters may not reduce infection and subsequent mortality by either dermo or MSX diseases when deployed during multiyear drought conditions, and the use of SPF seed in most areas when such conditions exist will not improve chances of survival. SPF juvenile oysters are more likely to survive and grow to market size if subjected to just one year of drought than oysters subjected to two years of drought, but their ultimate success will remain a function of the salinity regime they experience.