The photooxidative removal of analgesic pharmaceutical compound phenazopyridine (PhP) from aqueous solutions by UV/H2O2 system with a re-circulated photoreactor was investigated. Response surface methodology (RSM) was employed to optimize the effect of operational parameters on the photooxidative removal efficiency. The investigated variables were: the initial PhP and H2O2 concentrations, irradiation time, volume of solution and pH. The analysis of variance (ANOVA) of quadratic model demonstrated that the described model was highly significant. The predicted values of the photooxidative removal efficiency were found to be in a fair agreement with experimental values (R2 = 0.9832, adjusted R2 = 0.9716). The model predicted that the optimal reaction conditions for a maximum removal of PhP (>98%) were: initial PhP concentration less than 23 mg L–1, initial concentration of H2O2 higher than 470 mg L–1, solution volume less than 500 mL, pH close to 2 and irradiation time longer than 6 min.