Response surface methodology (RSM) using D-optimal design was applied to optimization of photocatalytic degradation of phenol by new composite nano-catalyst (TiO 2 /Perlite). Effects of seven factors (initial pH, initial phenol concentration, reaction temperature, UV irradiation time, UV light intensity, catalyst calcination temperature, and dosage of TiO 2 /perlite) on phenol conversion efficiency were studied and optimized by using the statistical software MODDE 8.02. On statistical analysis of the results from the experimental studies, the optimum process conditions were as follows: initial pH, 10.7; initial phenol concentration, 0.5 mM; reaction temperature, 27 o C; UV irradiation time, 6.5 h; UV light intensity, 250 W; catalyst calcination temperature, 600 o C; and TiO 2 /perlite dosage, 6 g/L. Analysis of variance (ANOVA) showed a high coefficient of determination (R 2 ) of 91.8%.