Background: Trans-tubular potassium gradient (TTKG) is considered to reflect mainly aldosterone bioactivity with regard to its kaliuretic response. We determined both TTKG and aldosterone serum concentrations in patients with severe drug-induced hyperkalemia (DIH). Methods: Ten hyperkalemic patients with serum potassium of more than 5.5 mEq/l, and serum creatinine of less than 2.5 mg/dl (221 µmol/l) were studied prospectively. Two control groups of 10 patients each were used. Control 1 group with normal renal function, and control 2 group with normokalemia and renal failure of the same magnitude as that of the hyperkalemic patients. Serum osmolarity, electrolytes, creatinine, aldosterone and urine electrolytes and osmolarity were measured and TTKG calculated. Results: DIH patients had lower TTKG values than control 1 patients (2.58 ± 0.36 vs. 6.68 ± 0.55, p < 0.001), and also lower than that of the control 2 patients (2.58 ± 0.36 vs. 5.51 ± 0.87, p < 0.01). Serum aldosterone concentration in the DIH group was higher than that of the control 1 group [24.30 ± 5.0 vs. 7.4 ± 2.1 pg/ml (674 ± 139 vs. 205 ± 58 pmol/l), p < 0.006] but not different from that of the control 2 group [24.3 ± 5.0 vs. 15.3 ± 3.8 pg/ml (674 ± 139 vs. 424 ± 106 pmol/l), respectively, p = 0.18]. Although there was some overlap in TTKG between DIH and control groups, 6 of 10 DIH patients had TTKG of less than 2.5, while none of the control patients had such a low value. Conclusion: DIH is characterized by lower TTKG values than those observed in patients with normal or mild-to-moderate renal failure. Other factors in addition to aldosterone seem to be involved.