Background: Both mechanical and phased-array catheters are used in clinical trials to assess quantitative parameters. Only limited evaluation of the in vivo agreement of volumetrical measurements between such systems has been performed, despite the fact that such information is essential for the conduction of atherosclerosis regression trials. Methods and results: We prospectively evaluated the agreement in morphometric measurements and intravascular ultrasound (IVUS)-based plaque characterization between a 40 MHz rotating transducer (3.2 F Atlantis, Boston Scientific Corp.) and a 20 MHz phased-array catheter (2.9 F Eagle Eye, Volcano Therapeutics, Rancho Cordova, California) in 16 patients. Lumen (7.3 ± 2.0 mm2 vs. 6.7 ± 1.8 mm2, p = 0.001) and vessel (11.8 ± 3.3 mm2 vs. 11.0 ± 2.9 mm2, p = 0.02) cross-sectional areas (CSA) were significantly greater with the 20 MHz system. Plaque CSA measurements showed no significant difference between systems (4.4 ± 2.3 mm2 vs. 4.4 ± 2.1). The relative differences were less than 10% for the three variables. On IVUS-based tissue characterization (13 patients), calculated percentage hypoechogenic volume was significantly higher for the 20 MHz system (96.7 ± 2.38 vs. 88.4 ± 5.53, p < 0.0001). Conclusions: Quantitative IVUS analyses display significant catheter type-dependent variability. It is unclear whether the variability reflects overestimation of measurements with the phased-array or underestimation with the mechanical system. Although plaque burden measurements did not differ significantly between systems, it appears prudent to recommend the use of a single system for progression/regression studies.