The Henderson-Hasselbalch equation and Stewart's strong ion model are currently used to describe mammalian acid-base equilibria. Anomalies exist when the Henderson-Hasselbalch equation is applied to plasma, whereas the strong ion model does not provide a practical method for determining the total plasma concentration of nonvolatile weak acids ([A(tot)]) and the effective dissociation constant for plasma weak acids (K-a). A simplified strong ion model, which was developed from the assumption that plasma ions act as strong ions, volatile buffer ions (HCO3-), or nonvolatile buffer ions, indicates that plasma pH is determined by five independent variables: PCO2, strong ion difference, concentration of individual nonvolatile plasma buffers (albumin, globulin, and phosphate), ionic strength, and temperature. The simplified strong ion model conveys on a fundamental level the mechanism for change in acid-base status, explains many of the anomalies when the Henderson-Hasselbalch equation is applied to plasma, is conceptually and algebraically. simpler than Stewart's strong ion model, and provides a practical in vitro method for determining [A(tot)] and K-a of plasma. Application of the simplified strong ion model to CO2-tonometered horse plasma produced values for [A(tot)] (15.0 +/- 3.1 meq/l) and K-a (2.22 +/- 0.32 x 10(-7) eq/l) that were significantly different from the values commonly assumed for human plasma([A(tot)] = 20.0 meq/l, K-a = 3.0 x 10(-7) eq/l). Moreover, application of the experimentally determined values for [A(tot)] and K-a to published data for the horse (known PCO2, strong ion difference, and plasma protein concentration) predicted plasma pH more accurately than the values for [A(tot)] and K-a commonly assumed for human plasma. Species-specific values for [A(tot)] and K-a should be experimentally determined when the simplified strong ion model (or strong ion model) is used to describe acid-base equilibria.