The pharmaceutical compounds were analyzed in 14 sampling sites and pointed out the pollution sources related to raw sewage input and urban drainage discharge. Five medicine compounds, one illicit drug, and its metabolite were the higher measured content using analytical improvements tailored to identify and quantify organic compounds in low water content. The use of SPE cartridges followed by liquid chromatography with tandem mass spectrometry (LC-ESI-MS/MS) points out the Guavirutuba tributary as the primary water pollution source with higher concentrations in 2011 for pharmaceuticals, cocaine, and benzoylecgonine (metabolite) in the range of 6.7 ?? 0.9 ng L???1 to 27.386 ?? 142 ng L???1. The Jaceguay stream also located in Guarapiranga was the most preserved area and provided analytical values correspondent which lowered contamination content. Such concentrations mean a possible and feasible water restoration target. The most common compounds (above 90% samples) were: caffeine, atenolol, carbamazepine, cocaine, and benzoylecgonine. The integrated risk index for aquatic chemical pollution (IRICAP) confirms the higher contamination near Guavirutuba stream and the lower near the Jaceguay stream. Published results of cocaine and benzoylecgonine content in Guarapiranga basin corroborated with the analytical results.Funda????o de Amparo ?? Pesquisa do Estado de S??o Paulo (FAPESP)Conselho Nacional de Desenvolvimento Cient??fico e Tecnol??gico (CNPq)FAPESP: 09/53898-9; 11/51064-3CNPq: 310214/203-0