The potential interaction between lithium and angiotensin-converting enzyme (ACE) inhibitors was investigated in a retrospective, longitudinal, case-control study of 20 hypertensive patients previously stabilized on lithium therapy. The objective of the study was to determine the impact of ACE inhibition on steady-state lithium concentrations and to evaluate the potential association of altered lithium clearance with age, renal function, and electrolyte balance. After initiation of the ACE inhibitor, steady-state lithium concentrations increased by 36.1%, lithium clearance was reduced by 25.5% (p < 0.0001), and four patients presented with symptoms suggestive of lithium toxicity. Significant bivariate correlations were observed for lithium clearance change and age (r = -0.45; p < 0.05) and for lithium clearance change and serum creatinine (r = -0.52; p < 0.02). Multiple regression analysis indicated that 25% of the change in lithium clearance was associated with a change in serum creatinine. This percentage was increased to 35% by the inclusion of age in the regression model. None of the other variables (age, height, weight, or change in serum sodium/potassium) made a significant contribution to this model. The authors concluded that a clinically important increase in lithium concentrations can occur in patients started on ACE inhibitor therapy. As elderly patients may be uniquely predisposed to this interaction, avoidance of this medication combination in older populations should be considered.