Objective To optimize the interventional treatment of coronary in-stent restenosis (ISR) by three-step algorithm with the precise guidance of optical coherence tomography (OCT). Methods This retrospective study was conducted in 32 ISR patients in the First Medical Center of Chinese PLA General Hospital from February 2019 to February 2021. A retrospective analysis was made of the clinical baseline data, surgical data, OCT data and follow-up outcomes. SPSS 13.0 was used for statistical analysis. Data comparison between groups was performed using t-test or χ² test depending on data type. Results The average age of 32 patients (30 males, 2 female) was (59.8±11.1) years. The mean left ventricular ejection fraction of all patients was (58.3±7.6)%. Percutaneous coronary intervention (PCI) targeted 27 left anterior descending arteries, 4 left circumflex arteries, and 5 right coronary arteries. According to Mehran′s classification, 13 was of pattern I, 9 of pattern Ⅱ, 10 of pattern Ⅲ, and 4 of pattern Ⅳ. The success rate of OCT-guided "three-step method" for ISR was 100.0% (32/32). OCT showed that the preoperative minimum lumen was (1.9±0.8) mm² with an area stenosis rate of (67.0±11.0)%, and the postoperative minimum lumen area was (5.0±1.3) mm² with an area stenosis rate of (24.0±10.5)%. Intraoperative DCB was used in 25 cases, DES in 10 cases, and ordinary balloon dilation in 1 case. No postoperative complications, postoperative cardiovascular adverse events, myocardial infarction and death occurred during the postoperative hospitalization. Among the 32 patients, 5(15.6%) developed angina within 6 months, including 1(3.1%) revascularization. One patient (3.1%) died of non-cardiac causes. Conclusion The three-step OCT guided interventional therapy for in-stent restenosis is safe and effective.