A three-dimensional computational fluid dynamics (CFD) study of heat transfer in a microchannel reactor for the low-temperature Fischer–Tropsch synthesis (FTS) is presented. The microreactor studied is a steel block with 80 square microchannels of 1 mm of side arranged in cross-flow configuration for the transport of syngas and cooling water. Syngas space velocities in the 5000–30,000 h−1 (STP) range have been considered. The microreactor exhibited good isothermicity under most simulated conditions. The FTS can be conducted with very low-temperature change between 483 and 523 K within a wide range of CO conversions using boiling water as coolant. To this end the pressure has to be set at the appropriate value between about 5 and 35 atm. The pressure would have to be reduced as the CO conversion increases which might have a negative effect on the FTS selectivity to middle distillates. However, adjusting the cooling water flow rate in the range 0.25–250 g min−1 allows maintaining the FTS temperature at suitable values while avoiding the use of low pressures. Relatively high values of the overall heat transfer coefficient in the 20–320 W m−2 K−1 range have been obtained. A significant effect of the buoyancy forces on the thermal performance of the microreactor has been found.