To evaluate in vivo the feasibility, safety, and paclitaxel (PTX) deliverability of a newly developed non-commercially available Paclitaxel-Coated Balloon (PCB) catheter in the swine healthy peripheral vein model. In total 12 PCBs were deployed in 12 venous segments. Primary feasibility endpoint was the successful application of the devices to the veins of the animals. Primary efficacy endpoint was the determination of the drug content in the venous tissue at 24 h and 7 days after balloon expansion, as assessed by analysis of the vein tissue with High Performance Liquid Chromatography (HPLC) coupled with tandem mass spectrometry. Primary safety endpoint was freedom from any major adverse event. Secondary endpoint was the investigation of any independent factor affecting the primary endpoints. Paclitaxel was detected in five out of six tissue samples 24 h post-intervention and five out of six tissues at 7 days following the procedure (10 tissue samples out of 12). The mean weight of tissue that was examined was 0.20604 ± 0.29822 g (range: 1.02823-0.03377 g) and the mean PTX concentration detected was 8.4 ± 13.1 μg/g (range: 0-36.1 μg/g). The average drug content detected at 24 h (17.1 ± 17.1 μg/g) was numerically superior, but non-statistically significant, compared to 7 days (3.1 ± 3.6 μg/g). An average of 33.8% of the drug remained on the balloon after retrieval. According to the multiple linear regression analysis, there was no significant correlation between transition time, PTX remaining on the balloon, time of analysis (24 h/7 days) and PTX tissue concentration. No abnormalities were noted during autopsy. The newly developed PCB successfully delivered within the healthy venous wall a dose of Paclitaxel that inhibits neointimal hyperplasia. No safety issues were raised at short-term follow-up.