Responses of polluted Onondaga Lake, New York, to early stages of a phased program to rehabilitate the lake from the effects of domestic waste inputs are documented. The analysis is based on more than 10 years of paired monitoring of the effluent (total ammonia and total phosphorus) of a wastewater treatment plant (WWTP) that discharges to the lake as well as the lake itself (including total ammonia, nitrite, total and dissolved forms of phosphorus, plankton biomass and composition, Secchi disc transparency, and zebra mussel density). Major reductions in total ammonia and total phosphorus loading relative to the preceding decade are reported for the WWTP for the November 1998 through October 1999 interval. Dramatic and, in some cases, unanticipated changes in the lake’s water quality and biota in response to the reductions in loading are documented for the April to October interval of 1999 including: (1) major decreases in total ammonia concentrations and improved status with respect to ammonia toxicity standards, (2) development of dense populations of zebra mussels, (3) decreases in fall concentrations of nitrite and improved status with respect to the related toxicity standard, (4) decreases in total phosphorus and total dissolved phosphorus concentrations, and (5) a severe Microcystis (phytoplankton) bloom that caused nuisance conditions and poor clarity. The zebra mussel invasion is attributed to the reductions in total ammonia concentrations to below toxic levels. The Microcystis bloom was probably related to the abrupt increase in the zebra mussel population. Additional reductions in phosphorus loading from the WWTP will be required to limit phytoplankton production and avoid the potential for continued nuisance conditions. Potential complications in resolving lake responses to future reductions in loading associated with the zebra mussel invasion are considered.