We evaluated the clinical application of a model of acid-base balance, which is based on quantitative physical chemical principles (Stewart model). This model postulates that acid-base balance is normally determined by the difference in concentration between strong cations and anions (strong ion difference [SID]), PCO2, and weak acids (primarily proteins). We measured electrolytes and blood gases in arterial blood samples from 21 patients in a medical or surgical intensive care unit or emergency room of a tertiary care hospital. The measured SID frequently differed from SID calculated from the measured blood components, which indicates that unmeasured cations or anions are present; these could not be accounted for by lactate, ketones, or other readily identifiable ions. We used an approach to acid-base analysis that is based on changes in base excess or deficit due to changes in: (1) free water as assessed by [Na+]; (2) in [Cl-]; (3) protein concentration; and (4) "other species" (ie, anion and cations other than [Na+], [K+], and [Cl-]). The contribution of "other species" was obtained from the difference between the SID measured and that predicted from Stewart's equation. It could also be calculated from the difference between the standard Siggaard-Anderson calculation of base excess and base excess attributable to free water, [Cl-], and proteins (ie, base-excess gap). Our results indicate that the SID gap, base excess gap, and anion gap reflect the presence of unmeasured ions, and both the anion-gap and base-excess gap provide readily available estimates of the SID gap. This provides a simple bedside approach for using the Stewart model to analyze the nonrespiratory component of clinical acid-base disorders and indicates that, in addition to unmeasured anions, unmeasured cations can be present.