The effects of the drug-coated balloon (DCB)-only strategy in the treatment of chronic total occlusion (CTO) coronary lesions remain controversial. Patients who underwent an in-stent restenosis (ISR) CTO percutaneous coronary intervention (PCI) had a significantly poorer prognosis than those who underwent a de novo CTO PCI. This retrospective analysis evaluated the efficacy and safety of the DCB-only strategy in the treatment of CTO lesions, and the factors associated with adverse events in the patients. Patients with CTO lesions who were treated with the DCB-only strategy from 1 January 2016 to 1 May 2021 were retrospectively enrolled in this study. The patients were stratified into the ISR and de novo (primary) groups. All the patients were re-admitted to the hospital and underwent clinical and/or angiographic follow-up. Of the 68 patients with CTO lesions, 38 (55.9%) were categorized as having ISR, and 30 (44.1%) were categorized as having de novo lesions. The outcomes measured included target lesion revascularization (TLR), lumen gain after intervention, and late lumen loss (LLL). After an average follow-up period of 16 months, a total of 15 patients experienced target lesion failure (13 in the ISR group and 2 in the de novo group). The rate of major adverse cardiac events (MACEs) was significantly lower in the de novo group than the ISR group (10% vs. 39%, P=0.004). There was a significant difference in LLL between the two groups, with the de novo group showing a decrease (-0.04±0.83 mm) and the ISR group showing an increase (0.97±1.45 mm) (P=0.03). The univariable Cox proportional hazard analyses revealed that the incidence of TLR was independently associated with the stenosis type (either ISR or de novo lesions) [odds ratio (OR): 7.28; 95% confidence interval (CI): 1.494-35.464; P=0.01]. Male gender (OR: 3.726; 95% CI: 1.014-12.818; P=0.03) and body mass index (BMI) (OR: 1.246; 95% CI: 1.022-1.518, P=0.03) were also associated with the incidence of TLR. However, after adjusting for the variables of age, gender, and BMI, no significant association was found between MACE occurrence and ISR (OR: 4.156, 95% CI: 0.734-23.522; P=0.11). Treatment using the DCB-only strategy was found to be beneficial for patients suffering from CTO coronary lesions, especially those presenting with de novo lesions.