We investigated the effects of a binary Ni-Zn mixture on chronic reproductive toxicity to the water flea Daphnia magna. The results suggested that the type of interactive effect is dependent on the effect size at which Ni and Zn are combined in the mixture. Weak antagonistic or non-interactive effects occurred in the mixture treatments where each of the individual metals produced insignificant or only weak adverse effects on their own. Conversely, synergistic mixture effects, i.e., stronger effects than expected, only occurred when at least one of both metals in the mixture caused a greater than 20% effect on reproduction. Since low effect sizes are the most relevant ones in most regulatory frameworks, our data suggest that the CA and IA mixture toxicity models can both serve as conservative models for predicting effects of Ni-Zn mixtures.