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This study evaluates the role of design, operational, and physicochemical parameters of constructed wetlands (CWs) in the removal of pharmaceuticals (PhCs). The correlation analysis demonstrates that the performance of CWs is governed by several design and operational factors (area, depth, hydraulic loading rate, organic loading rate, and hydraulic retention time), and physicochemical parameters (dissolved oxygen, temperature, and pH); the removal efficiency of about 50% of the examined PhCs showed a significant correlation with two or more factors. Plants contributed significantly in the removal of some of the PhCs by direct uptake and by enhancing the process of aerobic biodegradation. The use of substrate material of high adsorption capacity, rich in organic matter, and with high surface area enhanced the removal of PhCs by adsorption/sorption processes, which are the major removal mechanisms of some PhCs (codeine, clarithromycin, erythromycin, ofloxacin, oxytetracycline, carbamazepine, and atenolol) in CWs. Although the removal of almost all of the studied PhCs showed seasonal differences, statistical significance was established in the removal of naproxen, salicylic acid, caffeine, and sulfadiazine. The effective PhCs removal requires the integrated design of CWs ensuring the occurrence of biodegradation along with other processes, as well as enabling optimal values of design and operational factors, and physicochemical parameters.