BACKGROUND: We aimed to validate a low-dose two-volume pulmonary computed tomography (CT) perfusion technique. METHODS: Five Yorkshire swine (weight 53.6 ± 2.6 kg) underwent 21 independent CT perfusion acquisitions. Intravenous contrast material (370 mg/mL iodine, 0.5 mL/kg) and saline chaser (0.5 mL/kg) were injected at 5 mL/s for each acquisition. Two-volume and multivolume dynamic CT perfusion data were acquired using a 320-slice CT, with multivolume measurements serving as the reference standard. The two-volume CT perfusion involved a low-dose (50 mA) volume scan before contrast injection and a diagnostic (300 mA) volume scan after bolus-tracking in the main pulmonary artery at the peak contrast enhancement. Multivolume CT perfusion included 15-20 volume scans for blood flow measurement. Paired sample t-test, linear regression, and Bland-Altman analysis compared both global and regional two-volume perfusion measurements to the reference standard. The reproducibility of the two-volume CT perfusion was assessed from two independent measurements under the same perfusion condition. RESULTS: Two-volume global perfusion measurements (P CONCLUSION: We successfully validated a prospective, two-volume CT perfusion technique in a swine model. The findings affirm the feasibility of accurate and reproducible pulmonary blood flow measurement. RELEVANCE STATEMENT: This two-volume CT pulmonary perfusion technique, validated in a swine model, demonstrates the feasibility of blood flow measurement with a substantial reduction in radiation exposure. It could allow low-dose regional blood flow measurement in the assessment of pulmonary artery disease in humans. KEY POINTS: Lung perfusion can be measured in mL/min/g using a prospective, two-volume CT technique. Flow measurement is achievable in a swine model with a radiation dose as low as 9.3 mGy. CT angiography and perfusion can be acquired following a single contrast injection.