The relation between the serum anion gap and the serum total carbon dioxide concentration was studied in 100 admissions of patients with diabetic ketoacidosis and 43 normal control subjects. In 20 admissions of patients with diabetic ketoacidosis (Group 1), the patients had no other conditions or medications known to alter acid-base or electrolyte homeostasis, whereas in 80 admissions of patients with diabetic ketoacidosis (Group 2), the patients had at least one of these factors. Analysis of the change in total carbon dioxide compared with the change in anion gap in Group 1 and control subjects revealed the following relation: change in total carbon dioxide = 0.74 + 1.00 X change in anion gap, in meq/liter (r = 0.886, p less than 10(-7]. The 95 percent prediction interval for detecting mixed acid-base disorders with this equation was +/- 8 meq/liter. Analysis of all admissions of patients with diabetic ketoacidosis and control subjects combined showed that the anion gap increased 0.24 meq/liter per mg/dl increase in blood urea nitrogen (with total carbon dioxide constant). Because the highest blood urea nitrogen level in Group 1 and control subjects was 22 mg/dl, the change in total carbon dioxide-change in anion gap regression is generally not valid for blood urea nitrogen levels higher than 22 mg/dl. Thus, both the wide prediction interval and volume depletion (as reflected by blood urea nitrogen level) impair the usefulness of the anion gap as a screen for mixed acid-base disorders in patients with diabetic ketoacidosis.