A wide variety of pharmaceuticals are discharged in water courses on a daily basis due to their incomplete removal from effluent in treatment plants. The aim of the current study was to assess the occurrence, fate and removal of pharmaceuticals from effluent and sludge samples collected in the biggest sanitary sewer plant in Southern Brazil. In total, 13 pharmaceuticals were detected in the influent through UHPLC-MS/M – paracetamol and caffeine recorded the highest concentrations, 137.98 and 35.29 µg L⁻¹, respectively. The treated effluent presented 11 compounds. Antibiotics were the class recording the widest diversity; metronidazole showed the lowest concentration (0.023 µg L⁻¹) and sulfamethoxazole presented the highest concentration (1.374 µg L⁻¹) in influent samples. Seven pharmaceuticals were absorbed by the sludge; among them, one finds caffeine, ciprofloxacin and ofloxacin, which were quantified both in the effluent and in the sludge. On the other hand, doxycycline, fenbendazole, norfloxacin and tetracycline were only detected in sludge samples – their concentrations ranged from 0.026 to 5.034 mg kg⁻¹. Clindamycin, oxytetracycline, sulfathiazole and trimethoprim concentrations increased throughout the treatment. There were high paracetamol and caffeine removal rates (>97%), and it may have happened due to degradation, photodegradation or chemical reaction. Ciprofloxacin and ofloxacin removal rate exceeded 83% mainly due to their sorption by sludge. Finally, the mass balance analysis highlighted high pharmaceutical loads (511.466 g d⁻¹) discharged into recipient waterbodies. This outcome demands broadening the removal of these pharmaceuticals from sewage. GRAPHICAL ABSTRACT