Even essential trace elements are phytotoxic over a certain threshold. In this study, we investigated whether heavy metal concentrations were responsible for the nearly complete lack of submerged macrophytes in an oligotrophic lake in Germany. We cultivated the rootless aquatic model plant Ceratophyllum demersum under environmentally relevant conditions like sinusoidal light and temperature cycles and a low plant biomass to water volume ratio. Experiments lasted for six weeks and were analysed by detailed measurements of photosynthetic biophysics, pigment content and hydrogen peroxide production. We established that individually non-toxic cadmium (3 nM) and slightly toxic nickel (300 nM) concentrations became highly toxic when applied together in soft water, severely inhibiting photosynthetic light reactions. Toxicity was further enhanced by phosphate limitation (75 nM) in soft water as present in many freshwater habitats. In the investigated lake, however, high water hardness limited the toxicity of these metal concentrations, thus the inhibition of macrophytic growth in the lake must have additional reasons. The results showed that synergistic heavy metal toxicity may change ecosystems in many more cases than estimated so far.