The release of pharmaceutical compounds to the environment, such as non-steroidal anti-inflammatory drugs (NSAIDs), implies a great concern because of its negative effects, e.g. potential cytotoxicity to liver and kidney of animal species. In the present study, a high-redox potential laccase is proposed as an alternative system for the biotransformation of selected NSAIDs: naproxen (NPX) and diclofenac (DCF). The effects of pH and the use of synthetic and natural mediators (1-hydroxybenzotriazole (HBT) and syringaldehyde (SA), respectively) were evaluated with the aim of optimizing the removal of NSAIDs by laccase. Results proved high removal yields for NPX (70-94%) after 24 h in the presence of HBT at acidic and neutral pH, while DCF was completely transformed at pH 4 within shorter periods, from 30 min to 4 h, both in the absence or presence of mediators. The operation at a higher pH implied the addition of mediators to remove DCF, with values of 50 and 95% for SA and HBT, respectively. Kinetic parameters of the transformation reactions and laccase deactivation were estimated and compared for the different experimental conditions. Besides, the identification of the major biotransformation products of DCF was attempted: decarboxylated compounds were detected by gas chromatography-mass spectrometry and corresponding reaction pathways were proposed. Moreover, laccase-catalyzed treatment was demonstrated to significantly improve the aerobic biodegradability of the medium containing DCF in comparison with untreated solution, suggesting that DCF transformation products are less toxic than the parent compound.