The extent of the depletion region at an n-ZnSe/GaAs heterointerface in MBE grown epilayers has been investigated by thickness-dependent Hall measurements. Exceptionally large depletion widths of up to 110 nm have been found on the ZnSe side. The depletion cannot be caused by charge transfer or interface states alone, but is attributed to compensation due to large scale atomic interdiffusion across the heterointerface. A II-VI buffer layer structure is demonstrated to shield the effects of the depletion from sensitive device layers grown on top, and to prevent parallel conduction by lateral and vertical transport through the substrate and the lower-lying buffer layers.