This paper focuses on the deactivation of a cobalt-based alumina-supported Fischer-Tropsch catalyst in a milli-fixed-bed reactor under different operating conditions. Different catalyst deactivation behaviors were observed at different syngas H-2/CO ratios and temperatures. The deactivation follows a two-step profile, where the initial deactivation is attributed to sintering, whereas the long-term deactivation is due to carbon deposition or cobalt oxidation on the surface. An unsteady-state semimechanistic model has been developed to represent the data at different temperatures and syngas ratios. This model takes into account cobalt sintering, coke deposition, and surface oxidation.