The Asian clam (Corbicula fluminea) co-occurs with unionid mussels in many riverine ecosystems. Clam populations can reach high densities and may undergo rapid die-offs, particularly during the low flow and warm temperatures of summer drought. Our study objective was to determine whether ammonia produced by decaying clam tissues during die-offs could affect unionid mussels. We induced C. fluminea die-offs in artificial streams to simulate die-off effects in natural habitats, and measured total and unionized ammonia (NH₃-N) and dissolved oxygen (DO) in the overlying water. When water flow was stopped, reductions in DO preceded the onset of mortality in streams having the highest density of clams (∼10,000 clams/m²). NH₃-N concentrations in the overlying water increased in association with clam mortality and reached concentrations of up to 5.04 mg/L at 26 ± 2°C. Temperature significantly influenced the rate of DO reduction and NH₃-N production in the systems, while resumption of water flow led to rapid dissipation of NH₃-N from the water column. We also conducted laboratory experiments to determine median lethal concentrations (LC₅₀s) of total ammonia and NH₃-N for glochidia and juveniles of the unionid mussel Villosa iris, adults of the unionid Pyganodon grandis, and juveniles and adults of C. fluminea. The 96-h LC₅₀s (24-h for V. iris glochidia) for NH₃-N ranged from 0.11 mg/L for V. iris glochidia to 0.8 mg/L for adult C. fluminea, indicating that NH₃-N levels produced by Asian clam die-offs have the potential to exceed acute effects levels for at least some species of unionid mussels.