We studied prospectively whether atherosclerotic progression in apolipoprotein-E knockout mice could be noninvasively and accurately measured by use of high-resolution ultrasonographic biomicroscopy. We examined the correlation between the ultrasonographic characterization of ascending aortic atherosclerotic plaque and plasma C-reactive protein, interleukin-1, and interleukin-6 levels in these mice. In 4 age groups (8, 16, 24, and 32 wk) of 8 male knockout mice each (atherosclerotic groups) and age-matched male C57BL/6 mice (control groups), we used ultrasonographic biomicroscopy to measure maximal plaque thickness or intima-media thickness in the ascending aorta. We compared the findings with corresponding histologic measurements, and we measured plasma C-reactive protein, interleukin-1, and interleukin-6 levels in each group. Mean atherosclerotic thicknesses and C-reactive protein and interleukin levels were significantly higher in each atherosclerotic group than in the control groups (all P <0.05). Ultrasonographically measured atherosclerotic thickness correlated well with histologic measurements of the same vascular regions (r=0.81, P <0.001). C-reactive protein levels increased concomitantly with age in the knockout mice, and ultrasonographically measured atherosclerotic thickness correlated with those levels (r=0.626, P <0.001). However, there was no correlation between plasma interleukin levels and atherosclerotic severity as measured by ultrasonographic biomicroscopy. In the apolipoprotein-E knockout mice, we found that measurements of intima-media or maximal plaque thickness by ultrasonographic biomicroscopy noninvasively and accurately detected atherosclerotic progression, that plasma C-reactive protein levels correlated with atherosclerosis, and that elevated plasma C-reactive protein levels correlated with atherosclerotic severity. © 2011 by the Texas Heart®Institute, Houston.