The potential of using Chlorella for biomass production for biofuels and other products on a large scale has been explored for many years. However, Chlorella cells are vulnerable to predation by protozoa, resulting in productivity loss. Poterioochromonas malhamensis, a mixotrophic predator flagellate, is regarded as one of the most dangerous grazers in Chlorella cultures on a commercial scale, as it can cause deterioration or collapse of microalgal mass cultivation in just a few days. There is a need, therefore, for effective and safe methods for protecting microalgal crops from grazing organisms. In this study, a chemical compound, ammonium bicarbonate (NH4HCO3), was used to control P. malhamensis in cultures of Chlorella sorokiniana under both laboratory and pilot-scale conditions. The results showed that 400 to 800 mg L-1 NH4HCO3 could effectively control P. malhamensis, and the 24-h mortality of P. malhamensis was as high as 94% in indoor experiments and 90% in outdoor ponds. Compared with the control groups, the biomass of Chlorella increased by 77% in indoor cultures and 95% in outdoor ponds when treated with NH4HCO3. In addition, microscopic observation indicated that NH4HCO3 could also effectively control other contaminants in outdoor cultures, such as some ciliates, amoebae and cysts. Molecular sequencing further revealed that NH4HCO3 might be effective in controlling other flagellates. Experiments assessing the influence of pH on toxicity of NH4HCO3 to P. malhamensis revealed, for the first time, that it was the NH3 of NH4HCO3, not the NH4+, or the total NH3-N (NH3 and NH4+), that killed P. malhamensis. Owing to its high toxicity to P. malhamensis and other contaminants, its relative safety to C. sorokiniana, and its low commercial price and ecological acceptability, addition of NH4HCO3 is considered to be a highly effective, safe, and cost-efficient way to control P. malhamensis contamination in mass cultivation of Chlorella.