Oxytetracycline (OTC) is a broad-spectrum antibiotic that resists biodegradation and poses a risk to the ecosystem. This study investigated the degradation of OTC by heat-activated peroxydisulfate (PDS) and peroxymonosulfate (PMS) processes. Response surface methodology (RSM) was used to evaluate the effect of process parameters, namely initial pH, oxidant concentration, temperature, and reaction time on the OTC removal efficiency. According to the results of the RSM models, all four independent variables were significant for both PDS and PMS processes. The optimum process parameters for the heat-activated PDS process were pH 8.9, PDS concentration 3.9 mM, temperature 72.9 degrees C, and reaction time 26.5 min. For the heat-activated PMS process, optimum conditions were pH 9.0, PMS concentration 4.0 mM, temperature 75.0 degrees C, and reaction time 20.0 min. The predicted OTC removal efficiencies for the PDS and PMS processes were 89.7% and 84.0%, respectively. As a result of the validation experiments conducted at optimum conditions, the obtained OTC removal efficiencies for the PDS and PMS processes were 87.6 +/- 4.2 and 80.2 +/- 4.6, respectively. PDS process has higher kinetic constants at all pH values than the PMS process. Both processes were effective in OTC removal from aqueous solution and RSM was efficient in process optimization.