We examined the processes influencing summer hypoxia in the mainstem portion of Chesapeake Bay. The analysis was based on the Chesapeake Bay Monitoring Program data collected between 1985 and 2007. Self-organizing map (SOM) analysis indicates that bottom water dissolved oxygen (DO) starts to be depleted in the upper mesohaline area during late spring, and hypoxia expands down-estuary by early summer. The seasonal hypoxia in the bay appears to be related to multiple variables, (e.g., river discharge, nutrient loading, stratification, phytoplankton biomass, and wind condition), but most of them are intercorrelated. The winterspring Susquehanna River flow contributes to not only springsummer buoyancy effects on estuarine circulation dynamics but also nutrient loading from the land-promoting phytoplankton growth. In addition, we found that summer hypoxia is significantly correlated with the late winterspring (FebruaryApril) northeasterlysouthwesterly (NESW) wind. Based on winterspring (JanuaryMay) conditions, a predictive tool was developed to forecast summer (JuneAugust) hypoxia using river discharge and NESW wind. We hypothesized that the late winterspring wind pattern may affect the transport of spring bloom biomass to the western shoal or the deep channel of the bay that either alleviates or increases the summer hypoxic volume in the midbay region, respectively. To examine this hypothesis, residual flow fields were analyzed using a hydrodynamic ocean model (Regional Ocean Modeling System; ROMS) between 2000 and 2003, two hydrologically similar years but years with different wind conditions during the spring bloom period. Simulation model results suggest that relatively larger amounts of organic matter could be transported into the deep channel in 2003 (severe hypoxia; frequent northeasterly wind) than 2000 (moderate hypoxia; frequent southwesterly wind).