The role of different operational parameters related to Fenton reactions (pH, concentration of Fe and HO, and reaction time) and of Cl and SO was investigated in the degradation of the azo dye Direct Red 81, expressed in terms of its decolorization. The factorial design and Pareto's charts showed that only Fe concentration and pH influence the decolorization under the conditions evaluated. So, only these parameters were optimized using the response surface model. Under the best experimental conditions (initial pH 2.5, 11 mg L Fe, 78 mg L HO, and 20 min of reaction), 94 % of decolorization was achieved. However, even under the these conditions, but in the presence of Cl and SO , a striking loss of efficiency was observed as the concentration of these ions was increased, due the formation of chloride- and sulfate-iron complexes and less reactive inorganic radicals (Cl and SO). The results show that the presence of Cl is more deleterious, since sulfate-iron complexes are more reactive towards HO, and the SO turns out to favor the degradation. On the other hand, the negative effect of Cl can be compensated by increasing the chloride concentration up to 300 mmol L. In addition, although a high degradation level has been obtained by monitoring the dye absorbance and by HPLC-UV, a low mineralization occurred, being generated degradation products of higher ecotoxicity to Vibrio fischeri, showing the need of subsequent studies to identify these compounds as well as the application of additional treatments aiming the complete mineralization of the dye.