This study was undertaken to evaluate whether, after long-term enalapril administration tachyphylaxis to the blockade of angiotensin II (Ang II) generation occurs. After a mean follow-up of 24 months, six patients taking enalapril once daily with or without an associated diuretic were studied for 7 h in hospital. Blood pressure, heart rate, plasma converting enzyme activity, angiotension I (Ang I), Ang II and aldosterone were measured before and 2, 4 and 6 h after the morning dose of enalapril. While blood pressure remained unchanged after drug administration, Ang II and aldosterone levels fell following enalapril to very low levels, similar to those observed during the initial study, at the time of peak effect of enalapril. After enalapril administration, there was no correlation between plasma Ang I and Ang II suggesting that blockade of Ang II generation was complete, excluding the possibility of Ang I related interference with the Ang II measurements. These results indicate that virtually complete angiotension converting enzyme inhibition can still be achieved after prolonged use of enalapril.