Here, we provide an algorithm that predicts solvent accessible surface area (SASA) using concentrated solution osmotic pressure data. Sheep hemoglobin monomer and beta-lactoglobulin are used for verification. Additionally, SASA for structurally unknown calf lens a-crystallin aggregate is predicted. Using osmotic pressure data, the predicted SASA value for sheep hemoglobin, 22,398 +/- 1,244 angstrom 2, was in excellent agreement with computational model predictions (24,304 angstrom 2-26,100 angstrom 2). Similarly, predicted SASA values for bovine beta-lactoglobulin in pH solutions of pH 5.1, 6.0, and 8.0, were 5,765 +/- 1,031 angstrom 2, 6,656 +/- 1,082 angstrom 2, and 9,141 +/- 1,060 angstrom 2, respectively, were in good agreement with the computationally determined SASA value (7,500 angstrom 28,628 angstrom 2). Predicted SASA for the aggregate of calf lens a-crystallin (800 kDa) was found to be 417,691 +/- 16,790 angstrom 2. These results illustrate that this novel method can provide an important experimental alternative in estimating SASA for proteins and, possibly, their complexes in solution. (C) 2011 American Institute of Chemical Engineers AIChE J, 2012