The direct synthesis of dimethyl ether (DME) from syngas is an exothermic process, which requires two different catalyst functions in the same reactor: methanol (MeOH) synthesis and dehydration to DME. The two functions can be intimately mixed in hybrid pellets, located on separated pellets or coupled in core@shell-engineered pellets. In this work, a multitubular fixed-bed reactor, loaded with the catalyst configurations mentioned above, has been investigated by mathematical modeling. It is shown that the different spatial distribution of the active phases has a drastic impact on reactor performance. Using the mechanical mixture of separated pellets, the DME yield is hindered by intraparticle diffusion limitations. The hybrid catalyst, minimizing the diffusion length between methanol synthesis and dehydration catalyst functions, provides better DME yield performances but higher hotspot temperatures and can suffer from deactivation issues due to the detrimental interaction between the two catalytic functions. The MeOH@DME configuration, which allows for a limited contact between the catalyst active phases, guarantees DME yields comparable to those of hybrid pellets while moderating the hotspot temperature.