Deactivation of a sulfided CoMo/MgAl2O4 catalyst during catalytic hydropyrolysis of beech wood in a fluid bed reactor was studied. The stability of the catalyst was investigated by converting approximately 5 kg of biomass and collecting the liquid and solid products for every 1 kg fed, using the same catalyst load. The total time on stream was 16.2 h. A secondary fixed bed hydrotreating reactor with a sulfided NiMo/Al2O3 catalyst was used after the fluid bed reactor to further deoxygenate the vapors. The condensed organics and C4+ gasses yield for each 1 kg fed was 22.2 ± 1 wt.%, which was variations within the experimental uncertainty. The CO and CO2 yield during the experiment increased from 14.9 to 18.2 wt.% daf, while the aqueous phase yield decreased from 38.0 to 35.1 wt.% daf from the first to the fifth kilogram fed. The change in CO, CO2, and aqueous phase yields was ascribed to a decrease in hydrodeoxygenation activity of the catalyst. The oxygen content in the condensed organic phase increased from 40 to 2832 ppm, indicating that deactivation of the catalyst in both the fluid bed and the HDO reactor occurred. Our previous study1 has shown that potassium, a known catalyst poison, is transferred from the biomass to the catalyst, and therefore the effect of doping the catalyst with 1.9 wt.% potassium was also investigated. The results were compared to a similar experiment with a fresh catalyst. Both experiments were performed without the downstream fixed bed HDO reactor to show the effect on the chemistry in the fluid bed reactor only. This showed that potassium decreased the catalyst’s cracking, hydrogenation, and hydrodeoxygenation activity. Doping the catalyst with potassium also increased the char and coke yield from 13.3 to 14.6 wt.% daf, indicating that potassium can act as a catalyst for polymerization of the pyrolysis vapors. Overall, the results shows promise for using CoMo based catalysts for catalytic hydropyrolysis, but also indicates that attention should be paid to catalyst deactivation.