The first report on the presence of pharmaceuticals in the wastewater impacted river appeared in the mid-1970s [1-3] followed by the first systematic works in the late 1990s [4]. Studies on the accumulation of pharmaceutically active compounds (PhACs) on aquatic organisms such as fish were not initiated until the beginning of the 2121st st century [5]. Fish tissues such as muscles can be considered as a bio-indicator of water pollution due to the direct exposure to wastewater borne contaminants in rivers. The methods for PhAC extraction from fish muscle includes solid-liquid extraction [6-8], enzymatic microwave-assisted extraction [6,9], ultra-sound extraction (USE) [10], pressurized liquid extraction (PLE) [11,12], solid-phase microextraction (SPME) [13], and rotary extraction [5,14]. The clean-up step usually relies on solid phase extraction (SPE) with various types of sorbents: florisil, alumina, silica gel, hydrophilic-lipophilic balance (HLB) and mixed-mode cation-exchange (MCX) [15-17], gel permeation chromatography, washing with hexane, liquid-liquid extraction, and freezing out [15,18] An alternative and revolutionary method for the simultaneous extraction and clean-up of pesticides in foodstuff [19] which recently has been used for the determination of PhACs in biological matrices is the so-called QuEChERS (for Quick, Easy, Cheap, Effective, Rugged and Safe). Few studies are dealing with the extraction of PhACs using QUuECH hERS in different matrices such as earthworms [18], vegetables [20], and bivalves [21].QuEChERS is based on liquid-liquid partitioning of the analytes between water and acetonitrile (MeCN) using salts to produce the effect of salting out, followed by a dispersive solid phase extraction (d-SPE). This procedure offers many advantages including basic instrumentation for application, small sample amounts, rapid extraction, and low waste volume, which results in a time-efficient method.The use of QuEChERs for the determination of PhACs from complex biological matrices, such as fish muscle, generates extracts that contain material prone to adversely affect the mass spectrometric analysis (co-extracts),