Drug-coated balloon (DCB) therapy promotes beneficial vascular remodeling after percutaneous coronary intervention. However, its mechanisms remain elusive. Given paclitaxel's neurotoxicity, the effects of paclitaxel (PTX)-DCB treatment on periarterial innervation are unknown. This study assessed the impact of PTX-DCB on periarterial innervation in porcine coronary arteries. Coronary arteries from twelve pigs were treated with balloon catheters across four groups: (1) uncoated balloon (POBA), (2) balloon with 3 µg PTX/mm2 (1 × 3), (3) balloon with 6 µg PTX/mm2 (1 × 6) and (4) two balloons each with 6 µg PTX/mm2 (2 × 6). Quantitative coronary angiography was performed before, during, and after balloon angioplasty, and at day 28 prior to sacrifice. Following sacrifice, tissue samples were taken for histological examination of periarterial nerve fibres. High-dose PTX treatment resulted in late lumen enlargement (+ 0.29 ± 0.60 mm) in the control angiography after 28d compared to POBA treatment (POBA vs. 2 × 6-PTX group (p = 0.0236). Sympathetic nerve fiber density did not differ between the untreated and balloon-treated segments in the POBA group (untreated: 386.5 ± 169.1 nerves/cm2, balloon: 328.5 ± 289.9 nerves/cm2, p = 0.6439) but was significantly reduced in the PTX-treated animals (1 × 3-PTX: untreated: 540.9 ± 216.2 nerves/cm2, balloon: 177.0 ± 130.5 nerves/cm2, p = 0.0020; 1 × 6-PTX: untreated: 546.5 ± 226.8 nerves/cm2, balloon: 142.4 ± 61.7 nerves/cm2, p = 0.0003; 2 × 6-PTX: untreated: 498.6 ± 404.0 nerves/cm2, balloon: 176.5 ± 103.4 nerves/cm2, p = 0.0478). PTX-DCB treatment significantly reduced the proportion of periarterial nerve fibers < 500 µm2 in the balloon-treated segment (p vs. untreated segment: POBA = 0.0267; 1 × 3-PTX = 0.0680; 1 × 6-PTX = 0.0028; 2 × 6-PTX = 0.0391). PTX-DCB therapy exerts previously unrecognized pleiotropic effects by reducing perivascular nerve fiber density, resulting in coronary denervation that may contribute to the luminal gain beyond antiproliferative effects.