This paper deals with an in-depth study of the physicochemistry of PES membrane cleaning when the membrane was fouled by skimmed milk ultrafiltration. The main target of the cleaning was protein removal from the active layer of the PES membrane as irreversible fouling was likely due to pore entrance blocking. Alkaline cleaning was restricted to pH and temperature that can be further used at industrial scale with a spiral membrane (pH 11.5-12.0, T = 50 degrees C), limitations due to glue and seals but not to PES itself. By cleaning UF-fouled membranes in a stirred reactor, it was shown that an efficient cleaning solution might have an interfacial energy close to gamma(L) = 25 mJ m(-2) and be mainly nonpolar. Comparisons of the cleaning efficiency obtained in the stirred reactor on a plate-and frame-pilot and on a spiral-wound pilot were made for various UF conditions, and the same conclusions can be drawn. However, cleaning under UF conditions also highlighted the limiting role of hydrodynamic conditions (pressure, velocity) on cleaning efficiency. In spiral geometry, the final water rinse appeared crucial and needs further optimisation, as it is time and water consuming. This study underlines the need of an approach combining physicochemistry and hydrodynamics for the optimisation of the entire cleaning step.