We determined the efficacy of carbon dioxide (CO2) for preventing larval (veliger) settlement of the invasive zebra mussel (Dreissena polymorpha) and compared the response of native juvenile mussels and macroinvertebrate and periphyton communities to hypercapnia. A microcosm system of control (ambient Camb) and CO2 treatments [low PCO2 (Clow)=35,094 µatm, and high PCO2 (Chigh)=66,685 µatm)] was supplied with river water for 11 weeks. We measured zebra mussel settlement, juvenile native mussel (Lampsilis cardium and L. siliquoidea) growth and condition, and macroinvertebrate and periphyton community composition. Zebra mussels settled in all Camb tanks (n=4) from early July through August compared to one mussel in a CO2 treatment tank over the same period. Native mussel growth, tissue condition, and shell condition were reduced in CO2, particularly in the highest treatment. Benthic biomass (excluding zebra mussels) was similar in Camb and Clow but was reduced in Chigh. Macroinvertebrate community composition differed among treatments due to greater abundance of Chironomidae in Clow and Oligochaeata in Chigh. Periphyton abundance and richness increased in both CO2 treatments and was driven by increases in Cyanobacteria, Bacillariophyta and Chlorophyta. Our results indicate that efficacious levels of CO2 (~35,000 µatm PCO2) for reducing biofouling by dreissenids are tolerable to most freshwater benthic taxa. Chronic elevated CO2 infusion (>35,000 µatm PCO2) may reduce native mussel growth and condition and alter benthic invertebrate and periphyton community composition. Further refinement of CO2 application strategies is needed to determine minimal effective dose and duration to prevent dreissenid settlement and minimize effects on nontarget organisms.