The influences of operating variables and the limitation of dual-tubular reactors in series for the tert-amyl methyl ether (TAME) synthesis process were investigated by computer simulation. The feed for the process is the Cg cut Of naphtha cracker (pyrolysis gasoline) followed with selective hydrogenation. The species in the feed were identified by gas chromatography, and the mole fraction data were used for activity coefficient calculation. The kinetic model proposed by Rihko et al. was used to simulate the tubular reactor in the TAME process, whereas the equations for the calculation of the mole-fraction-dependent activity coefficients were incorporated into the model. The reliability of this work for the activity coefficient calculation was justified by performance tests of a commercial plant, while the validation of the model was further checked by the normal operation results of the plant. The investigation of operating variables, such as the molar ratio of methanol to isoamylene, space velocity, and feed temperature, indicated that the effect of operating variables of the first reactor on isoamylene conversion is much more significant than that of the second one. Moreover, after the optimization of the first reactor, the isoamylene conversion in the second reactor is only about 8.5%. The results suggest that for the improvement of process efficiency, the replacement of the second reactor with a catalytic distillation tower is necessary.