The optimization of the Catalytic Wet Peroxide Oxidation (CWPO) assisted by an Al/Fe-pillared clay (Al/Fe-PILC) was assessed in the inactivation of the MS2 coliphage in the presence of a synthetic surrogate of natural organic matter (NOM). The simultaneous effect of two experimental factors (i) H2O2 dose - (H2O2)d (3.00–25.50 % of the H2O2 theoretically required for full mineralization) and (ii) catalyst concentration (0.33–2.60 g/L), and four non-controllable variables (covariates) (a) circumneutral pH (6.00–9.00), (b) temperature (5.00–25.0 °C), (c) synthetic NOM concentration (2.0–20.0 mg C/L) and (d) MS2 titer (104, 105 and 106 PFU/mL) was investigated by Response Surface Methodology (RSM). Every response was modeled and maximized: (1) MS2 inactivation, (2) fraction of reacted H2O2, (3) decolourization and (4) NOM mineralization. Multi-response optimization via desirability function based on responses (1) to (3) achieved excellent fitting (0.94 out of 1.0) and following set of optimal experimental conditions: 0.33 g Al/Fe-PILC/L, 3.36 % (H2O2)d ​(Feactive/H2O2) = 0.46, giving rise to 92.9 % of MS2 inactivation and 100 % of reacted H2O2 at pH 7.07, 25.0 +/- 0.1 °C, 16.06 mg C/L as starting NOM concentration, and MS2 titer of 106 PFU/mL after just 70 min ​of reaction.