The recent history of loading of total ammonia (T-NH3) and organic nitrogen (N) from a pharmaceutical manufacturing facility to a municipal treatment plant (Metro) in Syracuse, New York, and the discharge of these constituents from Metro to N-polluted Onondaga Lake is documented. Further, the benefit of the implementation of pretreatment at the pharmaceutical plant, and the effect of an upset event at this treatment facility on loading to Metro and the lake and inlake concentrations are also documented. Models are used as analytical tools to couple loading and in-lake concentrations, to delineate the role that this pharmaceutical facility has played in the lake's ammonia pollution problem, and to evaluate the potential implications of future pretreatment upset events for the success of a rehabilitation program that is underway for the lake. The responsiveness of the lake to reductions in external loading is established by the lower T-NH3 concentration observed in the upper waters of the lake in the spring of 1999. Model analysis demonstrates this reduction was primarily (approximately 75%) because of the decrease in loading from the pharmaceutical facility achieved by pretreatment. An abrupt increase in loading in May 1999 associated with an upset event at the pretreatment facility caused a corresponding increase in the T-NH3 concentration of the lake of approximately 0.5 mg N/L. Model projections demonstrate that the load from the pharmaceutical plant before construction of the pretreatment facility exacerbated the lake's ammonia problems by increasing the occurrence and margin of violations of the toxicity standard. Continued upset events at the pretreatment plant could compromise the lake rehabilitation program.