The application of reverse osmosis (RO) in water intended for reuse is promising for assuring high water quality. However, one significant disadvantage is the need to dispose of the RO retentate (or reject water). Studies focusing on Pharmaceutical and Personal Care Products (PPCPs) have raised questions concerning their concentrations in the RO retentate. Advanced oxidation processes (AOPs) are alternatives for destroying these compounds in retentate that contains high concentration of effluent organic matter (EfOM) and other inorganic constituents. Twenty-seven PPCPs were screened in a RO retentate using solid phase extraction (SPE) and UPLC-MS/MS, and detailed degradation studies for 14 of the compounds were obtained. Based on the absolute hydroxyl radical (HO•) reaction rate constants for individual pharmaceutical compounds, and that of the RO retentate (EfOM and inorganic constituents), it was possible to model their destruction. Using excitation-emission matrix (EEM) fluorescence spectroscopy, the HO• oxidation of the EfOM could be observed through decreases in the retentate fluorescence. The decrease in the peak normally associated with proteins correlated well with the removal of the pharmaceutical compounds. These results suggest that fluorescence may be a suitable parameter for monitoring the degradation of PPCPs by AOPs in RO retentates.