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Understanding the natural variability of coastal ecosystems, and in particular distinguishing between the natural fluctuations and the ones that are caused by anthropogenic interventions and long-term climatic variability, is a major concern for establishing adequate management and adaptation strategies. The Aveiro lagoon, a shallow coastal lagoon (Portugal), holds one of the largest saltmarshes and saltpans in Europe and is a very important ecosystem from both economic and ecological viewpoints, making the protection of its water masses a requirement. To better understand the variability of its ecosystem, the factors controlling seasonal, inter-annual and long-term variability of the water quality in the Aveiro lagoon were thus analyzed. The statistical analysis was based on a set of climatic, hydrological and water quality observations undertaken between 1985 and 2010. Seasonal variations were mostly related with the seasonal variation of the main climatic and hydrological drivers, while long-term shifts were typically driven by the anthropogenic interventions in the lagoon. After the adoption of secondary treatment for industrial effluents on 1992, a recovery from hypoxia conditions occurred in the upstream area of the lagoon. After 2000 lower concentrations of silicates occurred downstream, and may also derive from some anthropogenic modifications (e.g., shunting of river water to the sewage system, deepening of the inlet) that may have affected the physical dynamics. In the downstream area of the lagoon, chlorophyll a presented a downward trend between 1985 and 2010 and lower concentrations after 2000, which were probably associated with the lower concentrations of silicates. Results from the data analysis showed that the seasonal, inter-annual and long-term trends observed in the Aveiro lagoon depend on the influence of both anthropogenic and climate drivers, putting in evidence the need to combine these different drivers when evaluating and developing management strategies for estuarine ecosystems.