We report a reversal in the sign of the herbivore-phytoplankton interaction between the zebra mussel (Dreissena polymorpha) and Microcystis aeruginosa, a harmful planktonic cyanobacterium. A pair of large-scale manipulations of mussel density in the same lake in consecutive years showed that when phosphorus concentrations were very low (mean total phosphorus [TP] ~ 3 µg L⁻¹), the effect of Dreissena on the biomass of M. aeruginosa was monotonically negative across the full range of sustainable mussel densities. When the enclosures were fertilized with phosphorus (mean TP ~ 9 µg L⁻¹), there was a monotonically positive effect of Dreissena on M. aeruginosa across the same mussel gradient. These contrasting results indicate that D. polymorpha feeds on M. aeruginosa, as shown in previous laboratory feeding experiments, but that the positive effects of D. polymorpha on M. aeruginosa can be larger than the negative effects of consumption. A sign reversal in the interaction between these two species is congruent with highly variable patterns in the response of M. aeruginosa to D. polymorpha invasion across lake and river systems in North America.