This study evaluated sonoporation in a xenograft model of pancreatic ductal adenocarcinoma (PDAC) using 4 different ultrasound contrast agents (UCAs) to select the optimal UCA for augmenting chemotherapy treatment. Athymic, nude, female mice (n = 120) were inocluated with MIA PaCa-2 cells in the right flank, and randomized into 2 control groups (vehicle or standard of care chemotherapy with paclitaxel and gemcitabine), and 8 treatment groups. These consisted of chemotherapy and one of 4 UCAs: Definity® (Lantheus Medical Imaging, N Billerica, MA, USA), Lumason® (Bracco, Milan, Italy), Optison™ (GE Healthcare, Princeton, NJ, USA) or Sonazoid™ (GE Healthcare, Oslo, Norway) scanned in a high or a low acoustic power cohort (ISPTA of 200 or 60 mW/cm2, respectively). Groups of 10 animals were treated once a week for 3 weeks with chemotherapy followed by a 10 minute infusion of one of the UCAs through a tail vein. Hemoglobin and oxygenation measurements were obtained weekly (at baseline, during treatment and 1 week post treatment) in subgroups (3 mice from each group) using 3D photoacoustic imaging on a Vevo 2100 LAZR scanner (Fujifilm Visualsonics, Toronto, Canada). The remaining mice were followed for tumor volume growth and survival. Groups were compared with two-way, repeated measures ANOVAs. Tumor volumes from the 4 treatment groups in the high acoustic power cohort were smaller than those of the group receiving chemotherapy alone (p<0.006). In the low acoustic power cohort, only mice receiving Definity showed a significant tumor volume reduction (p=0.003). Hemoglobin and oxygenation values across tumors were greater in the high acoustic power cohort (p<0.001), while the impact of UCAs was statistically significant for oxygenation (Definity and Sonazoid; p<0.05) and for hemoglobin within areas of detected blood flow (Optison; p=0.014). Hence, chemotherapy treatment of PDAC xenografts can be augmented with high acoustic power sonoporation, and Sonazoid appears promising as a sonoporation agent as we move towards a clinical trial in PDAC patients.