We monitored cage-based populations of the eastern oyster Crassostrea virginica in coastal waters of New York Harbor in 2 phases of sampling, 1 with localities spread out over the New York—New Jersey Harbor area (started 2008) and another with 3 localities within Jamaica Bay (started 2010), all impacted by high nitrogen input, low dissolved oxygen, but over a water quality gradient. Patterns of growth, mortality, condition, and disease were compared with a clean—water site in Shelter Island, NY, sampled in parallel with both sampling phases. In both studies, oyster mortality in the urban sites increased dramatically during and after the second summer growth season. Mortality also increased at the same time period at the cleanwater site, but to a much smaller degree. One instance of high mortality in the Lower Hudson was caused by MSX; but, otherwise, no known diseases were identified as the main cause of the sudden mortality increases. Our results suggest that a general effect of reduced water quality had a cumulative effect on the New York Harbor-emplaced oysters, which culminated in high mortality, mainly at the end of the second summer growing season. Despite the increased mortality, other factors such as soft tissue growth and reproduction were not reduced in the harbor sites relative to the clean-water control site. The vulnerability of oysters grown in impacted waters may have to be factored in attempts to restore oysters to impacted harbor waters.