The purpose of this article was to determine whether applying negative or positive pressure to perfluorocarbon-containing microbubbles before intravenous injection would improve the myocardial contrast when using newer imaging techniques such as harmonic and intermittent imaging. Perfluorocarbon-containing microbubbles were exposed to sustained negative or positive pressure before intravenous injection in 10 dogs. Microbubble size distribution and concentration were measured after each exposure. Peak myocardial videointensity with intermittent harmonic imaging with each sample was compared. Microbubbles exposed to -200 mm Hg pressure before intravenous injection produced both the highest concentration of microbubbles and greater numbers of microbubbles less than 4 microns. Peak myocardial videointensity did not correlate with microbubble concentration or size but did correlate with the absolute number of microbubbles < 4 microns (mean r value 0.76, range 0.61 to 0.90). Risk area was best visualized with perfluorocarbon-containing microbubble samples containing the smallest microbubbles. We conclude that the myocardial contrast observed with perfluorocarbon-containing microbubbles can be enhanced by applying negative pressure before injection. The mechanism for this improved contrast appears to be related to creation of smaller microbubbles.