The U.S. Food and Drug Administration designed the trough-to-peak ratio as an instrument for the evaluation of long-acting antihypertensive drugs, but the ratios are usually reported without accounting for interindividual variability. This study investigated how the trough-to-peak ratio would be affected by interindividual and intraindividual variability and by smoothing of the diurnal blood pressure profiles. The ambulatory blood pressure was recorded on placebo in 143 hypertensive patients (diastolic pressure on conventional measurement >95 mm Hg), After 2 months, the recordings were repeated on 10 mg (n=66) or 20 mg (n=77) lisinopril given once daily between 7 and 11 PM. The baseline-adjusted trough-to-peak ratios were determined from diurnal blood pressure profiles with 1-hour precision. Lisinopril reduced (+/-SD) the 24-hour pressure by 16+/-17 mm Hg for systolic and 10+/-10 mm Hg for diastolic (P<.001). According to the usual approach, disregarding interindividual variability, the trough-to-peak ratio was 0.72 for systolic pressure and 0.67 for diastolic pressure. In the 143 patients the ratios were not normally distributed. They were the same on both lisinopril doses. When interindividual variability was accounted for, the median trough-to-peak ratio was 0.34 (P-5 to P-95 interval, -0.46 to 0.87) for systolic pressure and 0.26 (-0.44 to 0.84) for diastolic pressure. In 66 patients examined twice on 10 mg lisinopril at a median interval of 32 days, the trough-to-peak ratios were characterized by large intraindividual variability. The median trough-to-peak ratios increased (P<.001) when the individual blood pressure profiles were progressively smoothed by substituting 1-hour averages by 2-hour moving averages (systolic/diastolic pressure, 0.41/0.27), 2-hour averages (0.43/0.29), 3-hour moving averages (0.42/0.34), or 3-hour averages (0.47/0.36). In conclusion, the trough to-peak ratio is idealized by not accounting for interindividual and intraindividual variabilities and by smoothing of the diurnal blood pressure profiles. If after review of its usefulness the trough-to-peak ratio is further instituted as an instrument in the evaluation of long-acting antihypertensive drugs, its determination and presentation must be regulated beyond the presently available recommendations.