1. Acute coronary syndromes are mostly the result of coronary plaque rupture. Diagnostic techniques focusing on the early detection of those plaques that are prone to rupture are still limited. Increased neovascularization in the adventitia and within the atherosclerotic plaque have recently been identified as common features of inflammation and plaque vulnerability. Contrast-enhanced intravascular imaging with microbubbles can be used to trace perfusion. 2. In the present study, we examined the perivascular network of the left anterior descending coronary arteries and left circumflex arteries of four domestic, clinically healthy pigs using intracoronary ultrasound after injection of microbubbles with a differential imaging technique (ACES; Computational Biomedicine Laboratory, University of Houston, Houston, TX, USA). Our aim was to detect blood flow into the coronary lumen and perivascular flow in contrast-enhanced images. Eleven regions of interest (ROI), including perivascular structures, were compared with regard to their grey scale level before and after the injection of SonoVue (0.06 mL/kg; Bracco Diagnostics, Princeton, NJ, USA). 3. A statistically significant (P = 0.018) enhancement was found in the echogenicity of the total perivascular space (adventitial region and perivascular vessels), as indicated by an increase in grey level intensity from 8.33 +/- 0.80 (before) to 10.11 +/- 0.88 (after microbubble injection). A significant enhancement of the 11 selected ROI (perivascular structures) was also recorded after the injection of microbubbles (from 7.92 +/- 2.14 to 14.03 +/- 2.44; P = 0.008). 4. We believe that the detection of perivascular structures with contrast-enhanced intracoronary ultrasonography combined with proper image processing may reinforce our future efforts in the detection of vasa vasorum, an active participant in the creation of acute coronary events.