The combination of an aldosterone receptor antagonist added to an angiotensin-converting enzyme inhibitor has been demonstrated to reduce cardiovascular and renal end points in hypertensive humans but can produce hyperkalemia in the common clinical setting of impaired renal function. We investigated the effects of dual therapy on acute and chronic potassium handling in hypertensive humans with renal impairment by conducting a randomized crossover clinical trial of 4 weeks of 40 mg lisinopril/25 mg spironolactone versus placebo in 18 participants with a glomerular filtration rate of 25 to 65 mL/min. Study end points, following an established protocol, were hourly determinations of dynamic renal potassium excretion (mmol/h) and serum potassium (mmol/L) after 35 mmol oral potassium challenge in addition to ambulatory potassium concentration. After 4 weeks, ambulatory potassium concentration was 4.87 mmol/L with lisinopril/spironolactone versus 4.37 with placebo (P<0.001). Lisinopril/spironolactone produced only a modest 0.44 mmol/h reduction in stimulated potassium excretion (P=0.03) but a substantial 0.67 mmol/L increase in serum potassium (P<0.001) in response to 35 mmol potassium; these findings are consistent with impaired extrarenal/transcellular potassium disposition. We found the increase in serum potassium after an oral potassium challenge to be a strong predictor of the increase in ambulatory potassium with lisinopril/spironolactone. Our study suggests that dual renin-angiotensin-aldosterone blockade may impair extrarenal/transcellular potassium disposition in addition to reducing potassium excretion in humans with renal impairment, and that acute changes in dynamic potassium handling are predictive of chronic changes in ambulatory potassium concentration with dual renin-angiotensin-aldosterone blockade.