The pre-oxidation of an extremely polluted pharmaceutical wastewater (chemical oxygen demand (COD) value of 362,000 mg/l) using the Fenton's reagent has been systematically studied using an experimental design technique. The parameters influencing the COD removal of the wastewater, namely temperature, ferrous ion and hydrogen peroxide concentrations have been optimized to achieve a COD global reduction of 56.4%. The total range of the proposed experimental design, however, could not be tested because under some conditions (hydrogen peroxide concentration over 5 M) the Fenton's reaction became violent and could not be controlled, probably due to the high exothermic effect associated with COD oxidation. For the tested conditions, the optimal values of hydrogen peroxide and ferrous ion concentration were 3 and 0.3 M, respectively, whereas temperature only showed a mild positive effect on COD removal. In addition, during the first 10 min of Fenton's reaction, more than 90% of the total COD removal can be achieved. Fenton's reaction has proved to be a feasible technique for the pre-oxidation of the wastewater under study, and can be considered a suitable pre-treatment for this type of wastewaters. (C) 2003 Elsevier B.V. All rights reserved.