To determine whether chemical additions can be used to reduce sludge production in biological wastewater treatment, uncouplers of respiratory adenosine triphosphate production were added to activated-sludge cultures. Effects of 12 uncoupling chemicals on cell yields in batch cultures were compared. The most effective of these chemicals, 2,4,5-trichlorophenol (TCP), was tested in a continuous-flow, bench-scale, completely mixed activated-sludge system treating simulated municipal wastewater. Initially, TCP addition reduced average yield by approximately 50%. After 80 days, sludge yield increased as TCP levels in the reactor decreased. Specific oxygen use rates were good indicators of sludge yields, increasing from 8 g O2/g volatile suspended solids (VSS)·d without TCP addition to approximately 20 g O2/g VSS·d, when sludge yield was lowest. These results suggest that addition of chemical uncouplers to biological wastewater treatment systems can significantly reduce sludge production, but long-term bioacclimation can eventually negate the effects of uncoupler addition.