The aim was to evaluate phase-inversion harmonic imaging (PIHI) with respect to brain perfusion imaging using a novel "bilateral approach" (depth of examination: 150 mm) and established unilateral approach (100 mm). After bolus injection of two contrast agents (CA, Optison and SonoVue), perfusion-related parameters (time-to-peak intensity, Itpk, peak intensity, Ipk, and peak width, Wpk) were extracted by fitting a model function to time-intensity curves for different regions-of-interest (ROI) in 14 volunteers. In 207 (92%) of 224 ipsilateral ROIs and in 165 (98%) of 168 contralateral ROIs (372 or 95% of 392 altogether), parameters could be derived. Itpk and Wpk of gray matter ROIs did not vary in or between both CA groups (18.1-21.9 s and 7.9-14.2 s). ROIs within arteries showed significantly shorter Itpk (16.1-16.7 s) and longer Wpk (12.8-28.3 s). Level of significance was 0.05 (two-sided). Newer CAs are usable for nonlinear imaging over a wider range of acoustic intensities, so that sensitivity of PIHI is sufficient to image the brain bilaterally. This approach proves to be reliable in patients with adequate bone windows. For acute stroke patients, this implies that both hemispheres can be compared in one instead of two examinations, reducing time of examination by 50%. Furthermore, evaluation of regions close to the probe becomes possible. Thus, the "bilateral approach" should be considered as a new standard approach of acute ultrasonic perfusion imaging.