The choice of the reference site in order to calculate percent luminal narrowing mainly depends on which diagnostic tool is used for examination. In intravascular ultrasound or histology, the local area encompassed by the internal elastic lamina (IEL) area is used as a reference. However, the local IEL area, and thereby the reference value, may have been altered by atherosclerotic remodeling. In the present study we examined the impact of local arterial remodeling on the calculation of luminal narrowing. Forty-five human femoral arteries were analyzed, 32 postmortem and 20 in vivo, by intravascular ultrasound. Cross sections were examined every 0.5 cm over an arterial segment length of 10 to 15 cm. In each cross section we measured the lumen area and the IEL area. Two reference areas were used to calculate percent luminal narrowing: (1) the lumen area in the cross section that contained the least amount of plaque (distant reference); and (2) the local IEL area (local reference). In each cross section, the IEL area was expressed as percent of the IEL area in the cross section that contained the least amount of plaque (relative IEL area). Using the distant reference, we found that less luminal narrowing was observed for cross sections with a relative IEL area > 100% (indicating compensatory enlargement) than for those with a relative IEL area < 100% (indicating shrinkage), whereas percent luminal narrowing calculated using the local reference hardly differed between cross section with a relative IEL area > 100% and < 100%. Thus, arterial wall remodeling makes the local IEL area an unreliable reference for calculation of percent luminal narrowing. The calculated percent luminal narrowing using a distant, nondiseased reference site reflects the actual change of the luminal area more accurately.