Increasing evidence indicates widespread occurrence of pharmaceuticals and personal care products (PPCPs) in municipal effluent discharges and surface waters. Studies that characterize the fate and effects of PPCPs in aquatic systems are limited, and to our knowledge, data regarding pharmaceutical accumulation in fish of effluent-dominated ecosystems have not been previously reported. In the present study, fish populations were sampled from a reference stream and an effluent-dominated stream in north Texas, USA. Lepomis macrochirus, Ictalurus punctatus, Cyprinus carpio, and Pomoxis nigromaculatus were killed; the liver, brain, and lateral filet tissues dissected; and the tissues stored at −80°C until analysis. Fish tissues were extracted using solid-phase extraction and then analyzed by gas chromatography-mass spectrometry in the negative chemical ionization mode. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline and the SSRI metabolites norfluoxetine and desmethylsertraline were detected at levels greater than 0.1 ng/g in all tissues examined from fish residing in a municipal effluent-dominated stream. To our knowledge, the present study is the first report of SSRI residues in fish residing within municipal effluent-dominated systems.