In this study, an electro-Fenton (EF) process with auto generation of Fenton's catalyst (Fe2+) was proposed and its applicability in degradation and mineralization of Ciprofloxacin (CIP) antibiotic was examined. A graphite-felt sheet was used as cathode for continuous electro-generation of H2O2 and a trifle stainless steel plate (AISI 304) was used as sacrificial anode to provide ferrous catalyst. Effect of various operating parameters including current intensity (5-100 mA), reaction time (5-25 min), initial CIP concentration (10-150 mg/L) and initial pH (2-7) was investigated using Response Surface Methodology (RSM). Central Composite Design (CCD) under RSM was utilized to model the two main responses, namely, CIP and COD removals. Simultaneous optimization of responses under current intensity of 75 mA, treatment time of 20 min, initial CIP concentration of 45 mg/L and initial pH of 5 showed that 95.1% and 57.4% of CIP and COD removal efficiency could be achieved, respectively. High coefficients of determination (R-2), for CIP and COD removal efficiency (0.92 and 0.94, respectively) indicated strong predictive capability of the models. BOD5/COD ratio, as an index of biodegradability, increased sharply from 0 to 0.42 under optimal condition. Two energy models, Electrical Energy Consumption (EEC) and EEC per unit COD removal, were introduced and the effect of operating parameters on them was evaluated. The intermediates of CIP degradation in aqueous solution were identified using ion chromatography and liquid chromatography coupled with mass spectrometry (LC-MS). (C) 2019 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.