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Sediment chemistry (total carbon [TC], total nitrogen [TN], total phosphorus [TP]), microbial respiration (dehydrogenase activity, DHA), and ecoenzyme activity (EEA) were measured in 4 zones of similarity in the northern Gulf of Mexico (GOM). DHA and EEA reflected the differences in C and N availability associated with proximity to the discharges of the Mississippi and Atchafalaya Rivers, and EEA represented the interface between microbial demands for, and environmental supplies of, nutrients. DHA was positively correlated with beta-glucosidase (BG, r = 0.30), [beta-N-acetyl glucosaminidase + L-leucine amino peptidase] ([NAG + LAP], 0.65), acid phosphatase (AP, 0.17), and aryl sulfatase (SULF, 0.42). EEAs were positively correlated with each other (0.34-0.76). DHA (0.22-0.33), [NAG + LAP] (0.46-0.64), and SULF (0.17-0.56) were positively correlated with TC, TN, and TP, while BG (0.58-0.60) and AP (0.50-0.58) were correlated only with TC and TN. Carbon use efficiency (CUE) and organic C decomposition rate (M), both based on ecoenzyme models, were positively correlated with TN and TC (0.43-0.46) and TC, TN, and TP (0.24-0.60), respectively. Modeled respiration (R-m), based on M, TC, and sediment bulk density, was correlated with sediment chemistry (0.17-0.90), and with DHA (0.50). All measured chemistry, DHA, EEA, and modeled decomposition parameters exhibited significant cruise, zone, and sediment depth effects, but few significant interaction effects. Structural equation modeling (SEM) revealed a causal relationship between sediment chemistry, EEA, and DHA, explaining 46% of the variance in DHA. As such, the relative activities of the functional classes of ecoenzymes are both a measure of nutrient availability and ecosystem metabolism that may be used to assess large-scale phenomena, such as regional impacts of anthropogenic disturbances.