In aquatic systems, some substances considered as endocrine disruptors have been detected, which can be due to their incomplete elimination in wastewater treatment plants (WWTPs) and inadequate disposal of pharmaceuticals. Among these contaminants are 17α-ethinylestradiol (EE2) and caffeine (CAF). Moreover, it has been reported that this kind of contaminants may provoke different adverse effects in many aquatic organisms. Because of that, in the present study, up-flow anaerobic sludge blanket reactors (UASB) coupled with the Fenton process was evaluated for EE2 and CAF removal spiked in wastewater samples. First, the best reaction conditions were established in each process. For UASB reactor, two hydraulic retention times (HRT 8 and 24 h) were evaluated, achieving the highest chemical organic demand (COD) removal (70%) and drug elimination (84-86%) with HRT 24 h. Subsequently, Fenton process was conducted at pH 3 with different levels of Fe (0.05-0.5 mmol/L) and molar ratios Fe:HO (1:1-1:10). Better results were obtained with 0.5 mmol Fe/L, and 1:10 ratio molar Fe:HO. Finally, UASB-Fenton coupled system allowed 80% of COD decrease, almost complete removal of drugs and the toxicity of samples on was reduced from 73 to 30%, demonstrating that this coupled system is a promising and efficient system for pharmaceutical compounds removal from wastewater.