The production of human interferon gamma (hlFN-${gamma}$) using a synthetic gene in Escherichia coli BL21-Sl was optimized by response surface methodology (RSM) and a Box-Behnken design. The process variables studied were temperature, biomass concentration at induction time and the NaGl concentration as inducer. According to the Box-Behnken design, a second order response function was developed. The optimal expression conditions were a temperature of $32.6^{circ}C$, induction biomass of 0.31g/L and 0.3M NaGl in minimal medium. The model prediction for the maximum hlFN-${gamma}$ production was 77.3mg/L, which corresponded satisfactorily with the experimental data. The hlFN-${gamma}$ concentration attained under optimized conditions was 13-times higher than that obtained using the non-optimized conditions. We conclude that RSM is an effective method for the optimization of recombinant protein expression using synthetic genes in E. coli.