Many studies demonstrate that the cumulative incidence of major adverse cardiovascular events (MACE) increase with a greater lesion length and smaller vessel size after DES implantation. OCT would provide operators with more accurate information about target lesions and a more comprehensive assessment of the stented segment during PCI. Whether it could provide benefit for the PCI procedure on small diffuse lesions remains undetermined. The aim of this study is to assess the efficacy and safety of optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) in patients with small diffuse coronary artery disease. The total study cohort included 587 consecutive patients who underwent PCI treatment for small diffuse lesions. Of these patients, 474 underwent procedures that were guided by angiography alone, while the remaining 113 patients underwent procedures that were guided by OCT. The patients presented for a 1-year follow-up after the index procedure. The primary endpoint was the 1-year incidence of major adverse cardiovascular events (MACE). Propensity score matching was performed for 113 pairs to eliminate the imbalance between the groups. During 1-year follow up, the MACE rate was lower in the OCT-guided group compared with the angiography-guided group (7.9% vs. 19.5%, P=0.001). This was mainly derived from the significantly lower TVR rate in the OCT-guided group (7.1% vs. 16.8%, P=0.04). Log-rank analyses demonstrated that the OCT-guided group had superior results to the angiography-guided group both before and after matching (P=0.01). The OCT-guided approach may improve efficiency and safety in long diffuse coronary lesions in small vessels.