Alappan and colleagues have shown that serum potassium levels significantly increase in patients receiving standard doses of trimethoprim-sulfamethoxazole [1]. Clinically significant hyperkalemia was more likely to occur in patients with some degree of renal insufficiency (serum creatinine level >106 mmol/L). Patients without renal insufficiency, although showing a similar absolute increase in serum potassium levels, were less likely to develop clinically significant hyperkalemia. This finding is not unexpected, given the amiloride-like action of trimethoprim in the distal tubule and the proven association between renal insufficiency and hyperkalemia due to amiloride use [2]. The authors, however, did not show any additive effect of other potassium-altering medications in causing the resultant elevation of serum potassium levels. This finding may be due to the definition of potassium-altering medications used in the study. If clinically significant drug interactions associated with amiloride that are known to result in hyperkalemia are used as a guide, only angiotensin-converting enzyme inhibitors, other potassium-sparing diuretics, and potassium supplementation should be used. The presence of concurrent renal insufficiency has been shown to enhance these interactions [3]. A reanalysis of the authors' data—one that identifies patients receiving the described medications and excluding patients whose potassium-altering medications consisted solely of heparin, digoxin, or a nonsteroidal anti-inflammatory drug—may clarify the expected additive interaction of trimethoprim and potassium-altering medications. Such a reanalysis may help clarify the role that renal insufficiency plays in this interaction. This information may help identify patients at significantly greater risk for hyperkalemia induced by trimethoprim-sulfamethoxazole.