Stratification and nutrient loading are two primary factors leading to hypoxia in coastal systems. However, where these factors are temporally correlated, it can be difficult to isolate and quantify their individual impacts. This study provides a novel solution to this problem by determining the effect of stratification based on its spatial relationship with bottom-water dissolved oxygen (BWDO) concentration using a geostatistical regression. Ten years (1998–2007) of midsummer Gulf of Mexico BWDO measurements are modeled using stratification metrics along with trends based on spatial coordinates and bathymetry, which together explain 27–61% of the spatial variability in BWDO for individual years. Because stratification effects explain only a portion of the year-to-year variability in mean BWDO; the remaining variability is explained by other factors, with May nitrate plus nitrite river concentration the most important. Overall, 82% of the year-to-year variability in mean BWDO is explained. The results suggest that while both stratification and nutrients play important roles in determining the annual extent of midsummer hypoxia, reducing nutrient inputs alone will substantially reduce the average extent.