Simple Summary Finding solitary pulmonary nodules (SPNs) during thoracic surgery, especially during minimally invasive procedures, remains a major challenge. Moreover, in cases of unclear focal findings, the frozen section result must be waited for, which influences the surgical procedure. Therefore, we are investigating for the first time the use of intraoperative contrast-enhanced ultrasound (Io-CEUS) in minimally invasive thoracic surgery to, on the one hand, visualize unclear SPNs, and on the other hand, to characterize the SPNs directly before surgical resection. In the future, Io-CEUS could make "live histology" possible in thoracic surgery, which may influence the surgeon's intraoperative decisions and the extent of lung resection. Background: The intraoperative detection of solitary pulmonary nodules (SPNs) continues to be a major challenge, especially in minimally invasive video-assisted thoracic surgery (VATS). The location, size, and intraoperative frozen section result of SPNs are decisive regarding the extent of lung resection. This feasibility study investigates the technical applicability of intraoperative contrast-enhanced ultrasonography (Io-CEUS) in minimally invasive thoracic surgery. Methods: In this prospective, monocentric clinical feasibility study, n = 30 patients who underwent Io-CEUS during elective minimally invasive lung resection for SPNs between October 2021 and February 2023. The primary endpoint was the technical feasibility of Io-CEUS during VATS. Secondary endpoints were defined as the detection and characterization of SPNs. Results: In all patients (female, n = 13; mean age, 63 & PLUSMN; 8.6 years) Io-CEUS could be performed without problems during VATS. All SPNs were detected by Io-CEUS (100%). SPNs had a mean size of 2.2 cm (0.5-4.5 cm) and a mean distance to the lung surface of 2.0 cm (0-6.4 cm). B-mode, colour-coded Doppler sonography, and contrast-enhanced ultrasound were used to characterize all tumours intraoperatively. Significant differences were found, especially in vascularization as well as in contrast agent behaviour, depending on the tumour entity. After successful lung resection, a pathologic examination confirmed the presence of lung carcinomas (n = 17), lung metastases (n = 10), and benign lung tumours (n = 3). Conclusions: The technical feasibility of Io-CEUS was confirmed in VATS before resection regarding the detection of suspicious SPNs. In particular, the use of Doppler sonography and contrast agent kinetics revealed intraoperative specific aspects depending on the tumour entity. Further studies on Io-CEUS and the application of an endoscopic probe for VATS will follow.