The one-step synthesis of methyl isobutyl ketone (MIBK) from acetone and hydrogen over Cu-on-MgO catalysts was studied at atmospheric pressure in a fixed bed continuous flow reactor. Catalysts with various copper loadings were prepared by impregnation and coprecipitation and characterized by BET and Cu(0) surface area measurements, XRD, SAXS, thermal analysis, and basicity measurements, A 3.46% Cu-on-MgO prepared by coprecipitation, calcined at 723 K for 4 h, and pretreated in hydrogen (673 K, 1 h) showed high and stable activity and selectivity in the production of MIBK. Under the best conditions (553 K reaction temperature, 15% molar excess of hydrogen to acetone, and 1920 mi h(-1) gcat(-1) space velocity) MIBK is formed in 45-48% yield (60-80% conversion and 60-75% selectivity) over a period of 24 h-on-stream. The results of deuterium labeling studies point to metallic sites catalyzing deuterium exchange and basic sites catalyzing dimerization of acetone, leading eventually to MIBK with high deuterium content, A comparison of deuterium contents of acetone, mesityl oxide (MO), and MIBK shows that the surface deuterium pool is highly diluted with hydrogen, formed during the exchange process. Deuterium incorporation during the saturation of the carbon-carbon double bond of MO to form MIBK therefore, is less than expected. Formation of diisobutyl ketone with very low deuterium content is suggested to result from the involvement of strongly bound surface intermediates with long residence time not allowing exchange process.