We compared five ion-selective electrodes (ISEs; AVL 985S, Baxter Lytening 2Z, Beckman EL-ISE, Ciba-Corning 654 Na/K/Li, and Nova CRT 11) and a colorimetric method (Ektachem) for determination of lithium with flame atomic absorption and atomic emission spectroscopy. We evaluated precision, recovery, interference by drugs (procainamide, N-acetylprocainamide, quinidine, lidocaine, carbamazepine, and valproic acid) and inorganic analytes (Na, K, Ca, Mg, and Br), and performance with sera from patients receiving lithium. Imprecision was < 5% (CV) for all analyzers except Ektachem and Beckman. Analytical recovery was 100% +/- 5% for all analyzers except Ektachem and Baxter. Some drug interference was seen with all analyzers except AVL and Corning. Calcium caused interference with AVL, Corning, and Ektachem analyzers, and sodium and potassium interfered with the Ektachem analyzer. The results with the Baxter, Beckman, and Corning analyzers were closest to those by flame atomic emission (mean differences, 0.01 to 0.02 mmol/L); the AVL and Nova analyzers gave lower results (mean differences, -0.11 to -0.13 mmol/L) and the Ektachem gave higher results (mean difference, 0.08 mmol/L).