A mathematic model that described the acid-base behavior of blood plasma has been revised to incorporate pK values of individual histidine residues on human serum albumin determined by nuclear magnetic resonance spectroscopy. With the insights derived from the model a method for evaluation of the strong ion difference has been developed. Thus if pH, PCO2, and the concentrations of serum albumin and phosphate are measured, all independent variables, which physically determine "acid-base balance" in plasma, can be quantified. New ways to evaluate "unidentified anions" in metabolic acidosis can be explored with this approach.