<p>A biocompatible membrane with superior nanofiltration ability was prepared from calcium alginate. To improve the filtration selectivity for small molecules (≤ 1200 Da), the membrane structure was modified using oligoethylene glycol (OEG) with an average molecular mass of 200 Da, similar to the target molecules for nanofiltration. The membrane structure involving with mass transfer was designed selectively for water permeation depended on the mass ratio of OEG as a void-forming agent to alginate as the base material of the membrane (<i>Φ</i>_OEG [ −]). OEG was added into the aqueous solution of sodium alginate before casting and removed after membrane crosslinking. The OEG-modified membrane showed high water permeation flux beyond the tradeoff relation between solution flux and solute rejection. The diameter of mass transfer channels estimated from the rejection of glucose, which is typical non-charged substance, was kept at nanofiltration region while decreasing the tortuosity of mass transfer channels. The effective diffusion coefficient of model solutes (180 Da ≤ molecular mass ≤ 1373 Da) increased as more voids were formed by OEG; however, the dependency of the effective diffusion coefficient on the molecular mass of model solutes was almost constant. Thus, biocompatible calcium alginate membrane with void-forming modification by OEG showed promising nanofiltration ability for small molecules.</p> Graphical Abstract <p></p>