The serum anion gap is often decreased in patients who have multiple myeloma or monoclonal gammopathy, presumably owing to the unmeasured contribution of cations by the paraprotein. In 83 patients who had moderate-to-severe diffuse (polyclonal) elevations in immunoglobulin concentration (>3 g/dl), the mean serum anion gap was significantly lower than in patients who had normal concentrations of immunoglobulin. In the subgroup with immunoglobulin levels greater than 4 g/dl, the mean anion gap was 8.7 mEq/l, compared with 11.9 for the control group (P < 0.001). Known causes of decreased anion gap, such as hyperkalemia or hypercalcemia, were absent. The albumin concentration had a minimal effect on the anion gap. The mean anion gap was independent of the patient’s diagnosis and the relative contribution of each immunoglobulin class to the total immunoglobulin. Thus, patients who have diffusely elevated immunoglobulin concentrations, as well as those who have monoclonal elevations, have a significantly lower mean anion gap. This low anion gap should be considered in the evaluation of the acid-base status of these patients.