The present study provides an environmental risk assessment of the pharmaceutical mixtures detected in Brazilian surface waters, based on Toxic Units and Risk Quotients. Furthermore, the applicability of a previously proposed prioritization methodology was evaluated. The pharmaceuticals were classified according to their properties (occurrence, persistence, bioaccumulation, and toxicity) and the contribution of the prioritized compounds to the mixture risk was determined. The mixture risk quotients, based on acute and chronic toxicity data, often exceed 1, demonstrating a potential risk for the environment. While algae were most affected by acute effects, fish were the most sensitive organism to sublethal effects. The lipid regulator atorvastatin was the main driver for the mixture risk. Despite their lower occurrence, the antibiotics norfloxacin and enrofloxacin were critical compounds for the algae group. The prioritized pharmaceuticals contributed to more than 75% of the mixture risk in most of cases, indicating the applicability of prioritization approaches for risk management.