Phenol red exhibits a slow rate of oxidation by laccase. A probable increase is suggested by the use of laccase-mediator systems (LMS). Nine compounds were tested and compared for their ability to act as mediators (I mM) in the Decolouriization of phenol red. Based on the dye decolorising ability, glycine and sulfanilic were selected as best mediators, achieving 64.63 and 63.8% decolourization, respectively with approximately 2.3 fold increase than the initial decolourization using laccase alone. The optimum conditions for attaining the highest decolourization were obtained at 30 h incubation time and 40°C in dark under acidic conditions (pH 4). The fact that glycine being among the best chosen mediators offers a non toxic alternative to commonly used mediators. The nature of glycine suggests electron transfer (ET) as a route of oxidation by LMS, while the decolourization by Fenton reagent (97%) suggests that hydroxyl (OH) radical to be a successful route for phenol red oxidation. A combination of both routes promises an escalation for the oxidation process of this dye.