A complete separation scheme has been designed for the effluent of a high-pressure ethanol-to-butanol catalytic reactor, producing 250,000 tonnes of n-butanol per year. The effluent contains water, hydrogen and a diverse range of C2-C4 oxygenates: unconverted ethanol, n-butanol, acetaldehyde, ethyl acetate, and acetal. Fundamental phase equilibrium relationships suggested use of conventional, extractive, and heterogeneous azeotropic distillation units to perform the separations. All reactor effluent species exit the separation process at mole purities of at least 99%. Separation costs are estimated to range from 9.0 to 10.6 MJ/kg n-butanol, which is comparable with the separation costs of n-butanol obtained from established acetone-butanol-ethanol (ABE) separation process.