A substantial part of the operating costs of wastewater treatment plants (WWTP) is associated with the management and treatment of the excess sludge generated during the treatment process. Different strategies have been applied for excess sludge reduction, such as the oxic-settling-anaerobic process, the high dissolved oxygen process, the uncoupler-containing activated sludge process, the ozonation-combined activated sludge process, control of sludge retention time and biodegradation of sludge in a membrane-assisted reactor. Chemical uncouplers have been shown to reduce excess sludge production, disassociating the energy coupling between catabolism and anabolism. These metabolic uncouplers may be organic compounds, such as 2,4-dinitrophenol (2,4-DNP) or 3,3',4',5-tetrachlorosalicylanilide (TCS), or heavy metals. In this paper, four different chemicals (2,4-DNP, TCS, copper (Cu) and zinc (Zn)) were chosen for short-term tests for studying their ability to reduce sludge yield (Y(x/s)) and, consequently, their potential for reducing excess sludge production. According to the results obtained, only TCS seems to be very effective in reducing sludge production from the activated sludge process. Compared with the control test, Y(x/s) can be reduced by over 30% at 0.8 mg/l TCS. It was also found that the substrate removal capability was not adversely affected by the presence of TCS. Furthermore, an increase in the microbial activity of the system was observed.