This chapter addresses the connections between long-term trends in climate variability, freshwater inflow dynamics, and salinity patterns and their effects on Perkinsus marinus infection of eastern oysters (Crassostrea virginica) at local and regional scales in Texas estuaries. Salinities were highest during droughts compared to normal and wet climatic conditions. At the local, within-estuary scale, salinities increased longitudinally from reefs closest to the freshwater inflow source to reefs closest to the Gulf of Mexico inlet. At the regional scale, salinities increased latitudinally moving from estuaries in the northeast to the southwest. Relationships between salinity and P. marinus infection levels were strongest for market size (≥76 mm) oysters. At the local scale, mean salinity had positive relationships with infection prevalence and severity of infection (= weighted prevalence) for market-sized oysters; salinity explained 94% of the variance in infection prevalence and 82% of the variance in severity of infection. Relationships at the regional scale were less strong; salinity was positively correlated with infection severity but not infection prevalence in market-sized oysters; salinity explained 64% of the variation in infection prevalence and 71% of variation in infection severity. Results were used to develop salinity recommendations of between 21.0 and 24.9 for maintaining low (≤50%) prevalence of P. marinus-infected oysters and low severity of infection (≤1.0) in order to support development of water resource management plans that account for variability in climate patterns.