Previous studies have used standard B-mode ultrasound to quantify the aggregate mean intimal medial thickness (IMT) of the near and far wall of the common carotid artery (CCA). Many investigators have had difficulty in accurately evaluating the near wall IMT secondary to difficulty in discerning the vessel lumen and intima. The purpose of this study is to determine the effect of contrast enhanced ultrasound on IMT measurement when compared with non-enhanced images. Twenty-six patients who had standard carotid ultrasounds completed over a 6-month period were evaluated, with 24 imaged by the same sonographer. Five to six measurements of the near and far walls were obtained over a 1 cm distance, beginning and ending 0.5 cm and 1.5 cm proximal to the carotid bifurcation. The measurements were made with and without the contrast agent Optison (perflutren protein type-A microspheres), which was given as an i.v. bolus (0.5-0.7 cc). Of those imaged by the same sonographer, 40 carotid arteries were examined and a total of 867 measurements were obtained. A total of 10% of the carotid ultrasounds were restudied approximately 1 month after the initial interpretation to assess observer accuracy. The near wall CCA mean (SD) IMT was 0.075 (0.019) cm for left with contrast versus 0.067 (0.023) cm for left without contrast and 0.089 (0.024) cm for right with versus 0.071 (0.022) cm for right without, p < or = 0.0001 both sides. For the far wall of the CCA, the mean (SD) IMT comparison was 0.075 (0.021) cm for left with versus 0.070 (0.016) cm for left without, p = 0.005, and 0.070 (0.023) cm for right with versus 0.070 (0.016) cm for right without, p = 0.68. In conclusion, contrast-enhanced IMT measurement showed a highly statistically significant difference in near carotid wall thickness determinations versus non-contrast values. The thicker measurement is in agreement with previously reported data showing that non-contrast images underestimated near wall common carotid IMT in histologic samples.