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Human activities are exposing freshwater ecosystems to a wide range of stressors, whose direct and indirect effects can be alleviated or exacerbated through interactive effects with dynamic environmental drivers. This study used long-term data from two Neotropical lacustrine freshwater systems (Batata Lake, an Amazonian floodplain lake and Imboassica lagoon, an Atlantic coastal lagoon) subjected to different kinds of environmental fluctuations (i.e., flood pulse and sandbar opening) and anthropogenic impacts (i.e., siltation and eutrophication). Our objective was to determine whether the effects of human perturbations are contingent on modifications of important biotic and abiotic characteristics through environmental variability. For both ecosystems, environmental variability consistently interacted with anthropogenic perturbations to alter most of the variables analyzed, such as nutrient dynamics, chlorophyll- a concentration, zooplankton and benthic invertebrate species richness, and temporal community stability, which indicates that interactive effects between environmental variability and anthropogenic perturbations may impact a myriad of ecosystem properties. Furthermore, the nature of these interactive effects was highly dependent on the variable considered and on the ecosystem analyzed. For example, at Imboassica lagoon, sandbar openings interacted synergistically with trophic state to increase the phosphorus concentration in the water column. At Batata Lake, flooding generally alleviated the negative effects of siltation on species richness by both diluting inorganic suspended material concentration and by promoting local recruitment from the regional species pool. Such results indicate that our ability to understand and predict the outcome of anthropogenic impacts on inland aquatic systems can be hampered if we consider human stressors as “static” phenomena disconnected from dynamic interactions with major local environmental drivers.