Understanding metal interactions with aquatic organisms is a key step to answer many questions about their nutritional importance, their accumulation and their toxicity. The Biotic Ligand Model (BLM) is a tool commonly used today to predict and quantify metal bioavailability for aquatic organisms. According to this paradigm, metal uptake and toxicity is determined by the binding of metal ions to key surface binding sites (biotic ligands) that will lead to internalisation. The extent of metal binding to biotic ligands depends on metal speciation (dissolved ligands compete with biotic ligands for metal binding) and on the presence of background cations such as calcium, magnesium and protons (cations and metals compete for binding with the biotic ligands).In recent years, metal mixtures have been investigated to identify antagonistic or synergistic effects. These studies usually examine the impact of two or more non-essential elements. However, little attention has been paid to the role of essential trace elements on the toxicity of another element. In this work, we examined if the use of low concentrations of essential elements (Co, Mn, Zn and Fe) modified the response of a freshwater green alga (Chlamydomonas reinhardtii) to copper. To do so, we followed cell growth over 72 h in exposure media where the essential element concentrations were manipulated. Among these elements, iron proved to have a strong impact on the cells’ response to copper. Dose-response curves showed that free Cu²⁺ concentrations required to inhibit cellular growth by 50% (IC50) over 72 h decreased from 2 nM in regular Fe medium ([Fe³⁺] = 10^-17.6 M) to 4 pM in low iron medium ([Fe³⁺] = 10^-19.0 M); a 500-fold increase in toxicity. These results show clearly that iron plays a protective role against copper toxicity to C. reinhardtii. This assertion is consistent with the results of Cu accumulation inside the algae during their exposures to Cu²⁺ under both low and regular iron conditions. From the accumulation curves, it appeared that, at low Cu²⁺ concentrations (pCu ~13.0 to pCu 10.5), Cu accumulation inside C. reinhardtii increases under low iron conditions but remain relatively stable under regular iron conditions. In this range of [Cu²⁺], copper accumulation reached up to ~150 amol·cell^-1 representing a 6-fold increase compared to that observed in algal cells grown in the regular iron medium. This last result confirms the plausible existence of protective effect of Fe³⁺ against Cu²⁺ uptake in C. reinhardtii. This protective role could partly be explained by the antagonistic effects between Fe³⁺ and Cu²⁺ at the binding sites of metals on the cell surface (i.e. BLM) but possibly also by a feedback mechanism linked to iron nutrition. We hypothesise that at low iron conditions, the cells increase the number and/or the affinity of iron transporters and that copper is internalised via this uptake mechanism, resulting in higher copper uptake and toxicity. In freshwaters, as opposed to marine waters, iron is always abundant. The expected free iron concentrations in surface waters can vary between 10^-14 to 10^-20 M, depending on pH (e.g. when pH increases from 6 to 8). We conclude that copper toxicity in natural waters can be modulated by iron geochemistry and that, in some conditions, the BLM may need to be further developed to account for the influence of iron.