The present work developed a model for the description of a full-scale wastewater treatment plant (WWTP) (Manresa, Catalonia, Spain) for further plant upgrades based on the systematic parameter calibration of the activated sludge model 2d (ASM2d) using a methodology based on the Fisher information matrix. The influent was characterized for the application of the ASM2d and the confidence interval of the calibrated parameters was also assessed. No expert knowledge was necessary for model calibration and a huge available plant database was converted into more useful information. The effect of the influent and operating variables on the model fit was also studied using these variables as calibrating parameters and keeping the ASM2d kinetic and stoichiometric parameters, which traditionally are the calibration parameters, at their default values. Such an ''inversion'' of the traditional way of model fitting allowed evaluating the sensitivity of the main model outputs regarding the influent and the operating variables changes. This new approach is able to evaluate the capacity of the operational variables used by the WWTP feedback control loops to overcome external disturbances in the influent and kinetic/stoichiometric model parameters uncertainties. In addition, the study of the influence of operating variables on the model outputs provides useful information to select input and output variables in decentralized control structures.