The occurrence of 130 pharmaceutically active compounds (PhACs) in sediments collected from 70 sampling sites in the Odra River estuary (SW Baltic Sea) was investigated. The highest concentration levels of the compounds were found in the vicinity of effluent discharge from two main Szczecin wastewater treatment plants: “Pomorzany” and “Zdroje”, and nearby the seaport and shipyard. The highest environmental risks (RQ > 1) were observed for pseudoephedrine (RQ = 14.0), clindamycin (RQ = 7.3), nalidixic acid (RQ = 3.8), carbamazepine (RQ = 1.8), fexofenadine (RQ = 1.4), propranolol (RQ = 1.1), and thiabendazole (RQ = 1.1). RQ for each compound varied depending on the sampling sites. High environmental risk was observed in 30 sampling sites for clindamycin, 22 sampling sites for pseudoephedrine, 19 sampling sites for nalidixic acid, 4 sampling sites for carbamazepine, and 3 sampling sites for fexofenadine. The medium environmental risk (0.1 < RQ < 1) was observed for 16 compounds: amisulpride, amitriptyline, amlodipine, atropine, bisoprolol, chlorpromazine, lincomycin, metoprolol, mirtazapine, moclobemide, ofloxacin, oxazepam, tiapride, tolperisone, verapamil, and xylometazoline. Due to the scarcity of toxicological data related to benthic organisms, only an approximate assessment of the environmental risk of PhACs is possible. Nevertheless, the compounds with medium and high risk should be considered as pollutants of high environmental concern whose occurrence in the environment should remain under close scrutiny.