Two pilot-scale experiments were conducted to investigate the syntheses of mesityl oxide (MO) and methyl isobutyl ketone (MIBK) from acetone using catalytic distillation (CD) technology. Commercial catalysts were utilized to obtain process benchmarks and to gain a cursory assessment of these processes. In the first CD experiment, MO was produced from acetone using Amberlyst-15 as a catalyst. The MO production and the product distribution were found to be governed by the reflux flow rate in the CD column. A process interaction is evident whereby the magnitude of the effect of the reboiler duty on the reflux flow rate is dependent on the system pressure. Significantly, the results of the first experiment clearly show that, by using CD technology, undesirable consecutive reactions can be minimized while the production of a desired intermediate species is simultaneously increased. In this case, the MO production was increased while the production of phorone, isophorone, mesitlyene, and other higher-molecular-weight products was simultaneously minimized by increasing the reflux flow rate in the CD reactor. Our first attempt to synthesize MIBK from acetone in a single stage in a CD reactor operating in continuous mode with two separate reaction zones was successful. However, the MIBK yield was relatively low, primarily because of hydrogenation catalyst deactivation and exacerbated by the relatively low system pressures used in the hydrogenation experiments, which ranged from 0.4 to 0.6 MPa. Although the mechanism of deactivation is unclear, experimental evidence suggests that MIBK is strongly adsorbed on the Pd/Al2O3 catalyst and might have contributed to catalyst deactivation.