A variety of mechanical and laser-based methods remove or shift atherosclerotic plaques and reopen the artery to its original lumen. Subsequent treatment with drug-coated balloons (DCB) may smooth the vessel wall but does not require high-pressure inflation. We investigated the efficacy of paclitaxel-coated balloons inflated with only 2 atm after bare metal stent implantation in coronary arteries of 24 pigs. Angiography and histomorphometry was performed on day 28. DCB inflated with 2 atm caused similar reduction of late lumen loss (LLL) as high-pressure inflation with 12 atm (0.89 ± 0.58 vs. 0.72 ± 0.39 mm, p = 0.34). Both DCB treatments significantly (p < 0.01) reduced LLL versus uncoated balloons (1.50 ± 0.51 mm). Treatment with low-pressure DCB resulted in less maximal intimal thickness (0.45 ± 0.15 vs. 0.67 ± 0.25 mm) and neointimal area (2.93 ± 0.73 vs. 3.82 ± 1.27 mm²) than treatment with uncoated balloons (p < 0.05). In conclusion, low-pressure treatment with DCB was similarly effective as high-pressure treatment justifying clinical trials in vessels which will benefit from inhibition of neointimal proliferation but may not tolerate high inflation pressure.