Dynamic light scattering and turbidimetry, carried out on solutions of hyaluronic acid (HA) and bovine or human serum albumin (SA) at fixed ionic strength (I), revealed a critical pH corresponding to the onset of HA-SA soluble complex formation. Subsequent reduction of pH below pH c , corresponding to an increase in protein net positive charge, results in phase separation of the complex. The sensitivity of pH c to I indicated the primacy of electrostatic interactions in this process. Since pH c was always above the pK a of HA, these effects could be attributed to the influence of protein charge. The electrostatic potential around HSA was modeled using DelPhi (MSI) under pH, I conditions corresponding to incipient binding, phase separation, and noninteraction. At all incipient binding conditions (i.e., pH c , at varying I), an identical region of positive potential 5 Å from the protein van der Waals surface appeared. This unique domain intensified with a decrease in pH or I (corresponding to stronger binding), and diminished with an increase in pH or I (i.e., at noninteracting conditions). The size and low curvature of this domain could readily accommodate a 12 nm (decamer) sequence of HA. Simple electrostatic considerations indicate an electrostatic binding energy for the formation of this complex of ca. 1 kT, consistent with the condition of incipient complex formation. We suggest that such weak electrostatic binding may characterize nonspecific interactions for other proteingylcosaminoglycan pairs.