A global uncertainty and sensitivity analysis (UA/SA) of a state-of-the-art, food-web bioaccumulation model was carried out. We used an efficient screening analysis technique to identify the subset of the most relevant input factors among the whole set of 227 model parameters. A quantitative UA/SA was then applied to this subset to rank the relevance of the parameters and to partition the variance of the model output among them by means of a nonlinear regression of the outcomes of 1,000 Monte Carlo simulations. The concentrations of four representative persistent organic pollutants (POPs) in two representative species of the coastal marine food web of the Lagoon of Venice (Italy) were taken as model outputs. The screening analysis showed that the ranking was remarkably different in relation to the species and chemical being considered. The subsequent Monte Carlo–based quantitative analysis pointed out that the relationships among some of the parameters and the model outputs were nonlinear. The nonlinear regression showed that the fraction of output variance accounted for by each parameter was strongly dependent on the range of the octanol–water partition coefficient (KOW) values being considered. For the less hydrophobic chemicals, the main sources of model uncertainty were the parameters related to the respiratory bioaccumulation, whereas for the more hydrophobic ones, KOW and the other parameters related to the dietary uptake explained the largest fractions of the variance of the chemical concentrations in the organisms. The analysis highlighted that efforts are still needed for reducing uncertainty of model parameters to get reliable results from the application of food web bioaccumulation models.