To determine the mechanism of action by which angiotensin-converting enzyme (ACE) inhibitors lower hematocrit in patients with posttransplant erythrocytosis, indices of red blood cell production and red blood cell destruction were obtained serially for 6 months from 10 renal transplant patients receiving treatment with enalapril for this problem. Before treatment, five patients had an elevated red blood cell mass, four had plasma volume contraction, and one had both. The mean hemoglobin concentration decreased by 2 g/dL (range, 0.5 to 3.3 g/dL), from 17 ± 1 g/dL to 15 ± 1 g/dL (P = 0.001) following 6 months of enalapril therapy. Similarly, the mean hematocrit decreased by 8% (range, 3% to 12%), from 52% ± 2% to 44% ± 3% (P = 0.001) during the same period. The mean reticulocyte count tended to decrease, although the change was not significant. The red blood cell mass decreased dramatically by 15% to 50%, from 32 ± 9 mL/kl to 23 ± 4 mL/kg (P = 0.008). Although serial erythropoietin levels declined steadily in two patients, there was no consistent change in the other patients. Mean levels decreased modestly, from 20 ± 11 mU/mL at baseline to 12 ± 5 mU/mL at 6 months, a change that was not statistically significant. Mean levels at each time point were not statistically different from the mean pretreatment value. Furthermore, during enalapril therapy, there was no correlation between mean circulating erythropoietin level and mean hematocrit (r = 0.43, P = 0.20) or hemoglobin concentration (r = 0.36, P = 0.30) or between changes in these parameters. Indices of red blood cell destruction, including haptoglobin, billrubin, and lactic dehydrogenase, were unchanged by enalapril therapy, as was calculated plasma volume at the beginning and end of the study. The current data suggest that enalapril improves posttransplant erythrocytosis by impairing red blood cell production without affecting red blood cell destruction or plasma volume. Furthermore, hematocrit decreased in most patients without a concomitant decrease in circulating erythropoietin levels. These results suggest that an inhibition of erythropoietin synthesis is not an essential component of the mechanism by which angiotensin-converting enzyme inhibitors lower hematocrit in most patients with posttransplant erythrocytosis. An inhibitory effect (ie, erythropoietin resistance) at the level of the bone marrow appears more likely, a hypothesis that would have to be proven by ferrokinetic studies in patients or by direct studies of erythropoiesis in vitro.