Diffusiophoresis is the migration of a particle in a fluid induced by the concentration gradient of another solute. We have experimentally investigated diffusiophoresis of a neutral macromolecule, poly(ethylene glycol) (PEG; molecular weight, 20 kg mol(-1)), in water induced by concentration gradients of osmolytes. Three osmolytes were examined: trimethylamine-N-oxide (TMAO), diethylene glycol (DEG), and urea. PEG diffusiophoresis coefficients were obtained from measurements of multicomponent-diffusion coefficients at 25 degrees C using Rayleigh interferometry. Osmotic diffusion coefficients, characterizing osmolyte diffusion from high to low PEG concentration, were also extracted. PEG diffusiophoresis was found to occur from high to low osmolyte concentration in all cases, with magnitude increasing in the order urea < DEG < TMAO. This ranking is consistent with that of osmolyte effectiveness in stabilizing protein native state. Osmotic diffusion coefficients, which allowed us to determine preferential-interaction coefficients, revealed that TMAO and DEG are preferentially excluded from the vicinity of PEG whereas urea was found to preferentially bind to this macromolecule. A novel model for macromolecule diffusiophoresis, which allowed us to examine the roles of preferential hydration, hydration, solute binding, and frictional dragging in this transport process, was developed. Our experimental results suggest that TMAO concentration gradients may be exploited to direct the motion of PEG and PEG-functionalized particles such as micelles, PEGylated proteins, and PEG-coated inorganic nanoparticles with potential applications to separation and adsorption technologies.