A mathematical model is presented that allows calculating the distribution concentration of low molecular-weight species (LMWS) interacting simultaneously with two high molecular-weight species in diafiltration experiments. This treatment may be used for the study of the interactions of LMWS with a water-soluble polymer (WSP) when surface fouling equilibrium on the diafiltration membrane is held, the simultaneous interaction with two WSP, or the coexistence of equilibria that may produce retention of the LMWS in the diafiltration cell, as molecular aggregation. For this treatment, it is assumed that the constants directing all the equilibria are kept independently of the presence of other connected equilibrium situations. Contrasting this treatment with previously described approximations. it is shown that significant differences are found in the calculation of the apparent dissociation constant between salicylic acid (SA) and branched poly(ethyleneimine) (BPEI), but not in the case of the interaction of triphenylterazolium chloride (T`TC) with poly(sodium 4-styrenesulfonate) (PSS), related with the respective sieving coefficient values for SA (0.54) and for TTC (0.91). (c) 2005 Elsevier B.V. All rights reserved.