Research focusing on biodiversity responses to the interactions of ecosystem size and anthropogenic stressors are based mainly on correlative gradient studies, and may therefore confound size-stress relationships due to spatial context and differences in local habitat features across ecosystems. We investigated how local factors related to anthropogenic stressors (e.g., eutrophication) interact with ecosystem size to influence species diversity. In this study, constructed lake mesocosms (with two contrasting volumes: 1020 (shallow mesocosms) and 2150 (deep mesocosms) litres) were used to simulate ecosystems of different size and manipulated nutrient levels to simulate mesotrophic and hypertrophic conditions. Using a factorial design, we assessed how the interaction between ecosystem size and nutrients influences phytoplankton diversity. We assessed community metrics (richness, diversity, evenness and total biovolumes) and multivariate community structure over a growing season (May to early November 2011). Different community structures were found between deep and shallow mescosoms with nutrient enrichment: Cyanobacteria dominated in the deep and Charophyta in the shallow mesocosms. In contrast, phytoplankton communities were more similar to each other in the low nutrient treatments; only Chlorophyta had generally a higher biovolume in the shallow compared to the deep mesocosms. These results suggest that ecosystem size is not only a determinant of species diversity, but that it can mediate the influence of anthropogenic effects on biodiversity. Such interactions increase the uncertainty of global change outcomes, and should therefore not be ignored in risk/impact assessment and management.