Laboratory research has suggested that isotonic contrast media may be optimal for intravenous digital subtraction angiography (IV-DSA) by generating taller, narrower time-concentration curves. Clinical investigation of low osmolality contrast media has suggested that less patient discomfort is encountered with low-osmolality contrast media than with standard, high-osmolality agents. In order to directly compare isotonic contrast media with a standard hypertonic contrast media, isotonic ioxaglate (Hexabrix-20) was compared with Renografin-76 in a double-blind prospective clinical trial for IV-DSA examination of the carotid artery bifurcation. Isotonic ioxaglate produced superior contrast medium time-opacification curves and produced superior images across four scales of image quality: anatomic "openness" of the carotid bifurcation, contrast level within the carotid vessels, bone misregistration artifact over the bifurcation, and air (soft tissue) misregistration. The bilateral overall score for isotonic ioxaglate was 1.68 vs. 1.37 for Renografin-76, a 23% superiority. The bulk of the superiority occurred in the contralateral carotid artery. Over the four scales, isotonic ioxaglate was 37% better in image quality of the contralateral carotid artery bifurcation. Since the contralateral carotid artery is very often difficult to visualize during IV-DSA, isotonic ioxaglate represents a significant improvement for this imaging modality.