Antibiotics are emergent contaminants that can induce adverse effects in terrestrial and aquatic organisms. The surface water compartment is of particular concern as it receives direct waste water discharge. Modeling is highlighted as an essential tool to understand the fate and behavior of these compounds and to assess their ecotoxicological risk. This study aims at testing the ability of the GREAT-ER model in simulating sulfamethoxazole (SMX) concentrations in the surface waters of the arid high-altitude Katari catchment (Bolivian Altiplano), assessing the sensitivity of the parameters considered, and evaluating the ecotoxicological risk posed. The model predicted the general spatial pattern of SMX concentrations. No contaminant abatement was observed during the wet season, supporting the idea that non-point sources, such as runoff and remobilization processes, play an important role during that season. During the dry season, the abatement capacity was 91%, suggesting that natural attenuation, particularly photodegradation, is high during low flow. Pharmaceutical consumption was the parameter that influenced the environmental concentrations the most. The ratio of Predicted Environmental Concentrations to predicted no-effect concentrations varied between 0.14 and 26.6 for the wet season and between 0.14 and 7.6 for the dry season depending on the river stretch.