In this study, Solid-phase micro-extraction (SPME) with Gas Chromatograph using Flame Ionization Detector (GC/FID) was studied as a possible alternative to liquid-liquid extraction for the analysis of Methyl tert-butyl ether (MTBE) and Tertiary-butyl ether (TBA) in water and an optimization condition of trace analysis of MTBE and TBA using the design of experiment (DOE) was described. The aim of our research was to apply experimental design methodology in the optimization condition of trace analysis of fuel oxygenated compounds in soil-phase microextraction with GC/FID. The reactions of SPME were mathematically described as a function of parameters of Temp ($X_1$), Volume ($X_2$), Time ($X_3$) and Salt ($X_4$) being modeled by the use of the partial factorial designs, which was used for fitting 2nd order response surface models and was alternative to central composite designs. The model predicted agreed with the experimentally observed result ($Y_1$(MTBE, $R^2$ = 0.96, $Y_2$ (TBA, $R^2$ = 0.98)). The estimated ridge of the expected maximum responses and optimal conditions for MTBE and TBA were 278.13 and (Temp ($X_1$) = $48.40^{circ}C$, Volume ($X_2$) = 73.04 mL, Time ($X_3$) = 11.51 min and Salt ($X_4$) = 12,50 mg/L), and 127.89 and (Temp ($X_1$) = $52.12^{circ}C$, Volume ($X_2$) = 88.88mL, Time ($X_3$) = 65.40 min and Salt ($X_4$) = 12,50 mg/L), respectively.