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The fate of glucocorticoids (GCs) in environment has been an increasing concern. In this study, performance of calcium peroxide (CaO2) in removing GCs was investigated using clobetasol propionate (CP) as the representative compound. Critical treatment parameters (including CaO2 dosage, initial pH, reaction time, and initial CP concentration) were optimized for CP removal by Response surface methodology (RSM) with a four-level Box-Behnken factorial design. A coefficient of determination (R2) value (0.97), model F-value (32.18) and its low p-value (F < 0.0001) along with lower value of coefficient of variation (9.35%) indicated the fitness of the model. The results showed that CaO2 treatment was effective in CP removal due to its coupled effects of oxidation and adsorption during CaO2 treatment. At optimum CaO2 dosage (3.43 g L-1), initial pH (7), reaction time (17.34 min), and initial CP concentration (0.03 mM), the model predicted 95.0% CP removal against the experimental value of 94.2% CP removal. Water matrixes influenced CP removal during CaO2 treatment in which HCO3 - ions played an inhibitory role. The highest removal efficiency was obtained in underground water, followed by in secondary effluent, in tap water, and in surface water. [ABSTRACT FROM AUTHOR]