Background: Clinicians calculate the anion gap (AG) and the strong ion difference (SID) to make acid-base diagnoses. The technology used is assumed to have limited impact. The authors hypothesized that different measurement technologies markedly affect AG and SID values. Methods: SID and AG were calculated using values from the point-of-care blood gas and electrolyte analyzer and the central hospital laboratory automated blood biochemistry analyzer. Simultaneously measured plasma sodium, potassium, and chloride concentrations were also compared. Results: Mean values for central laboratory and point-of-care plasma sodium concentration were significantly different (140.4 ± 5.6 vs. 138.3 ± 5.9 mM; P < 0.0001), as were those for plasma chloride concentration (102.4 ± 6.5 vs. 103.4 ± 6.0 mM; P < 0.0001) but not potassium. Mean AG values calculated with the two different measurement techniques differed significantly (17.6 ± 6.2 mEq/1 for central laboratory vs. 14.5 ± 6.0 mEq/1 for point-of-care blood gas analyzer; P < 0.0001). Using the Stewart-Figge methodology, SID values also differed significantly (43.7 ± 4.8 vs. 40.7 ± 5.6 mEq/1; P < 0.0001), with mean difference of 3.1 mEq/1 (95% limits of agreement, -3.4, 9.5 mEq/1). For 83 patients (27.6%), differences in AG values were as high as 5 mEq/1 or more, and for 46% of patients whose AG value was outside the reference range with one technology, a value within normal limits was recorded with the other. Conclusions: Results with two different measurement technologies differed significantly for plasma sodium and chloride concentrations. These differences significantly affected the calculated AG and SID values and might lead clinicians to different assessments of acid-base and electrolyte status.