Abstract Introduction Atherosclerotic plaque healing is a dynamic process that promotes plaque repair after destabilization. Previous studies showed that healed plaques are more common in patients with chronic coronary syndrome than in those with acute coronary syndrome, suggesting that they might be a marker of clinical stability. The mechanisms underlying plaque healing are not completely understood. The aim of the present study was to evaluate sex-based differences in plaque phenotype and healing of non-culprit coronary lesions by optical coherence tomography. Methods In this observational, single-center cohort study, we enrolled patients from the OCT Registry of the Fondazione Policlinico A Gemelli IRCCS. A total of 205 patients with both acute coronary syndromes or chronic coronary syndromes undergoing coronary angiography and intravascular OCT imaging of non-culprit vessels were included in the analysis and divided into two groups according to gender. Results Of 205 patients, 153 were male (75%) and 52 (25%) female. Compared with male patients, female patients had lower prevalence of lipid-rich plaque (40.4% vs. 57.7%; p=0.030), plaque rupture (7.7% vs. 21.2%; p=0.028) and cholesterol crystal (13.5% vs. 29.5%; p=0.022). Mean lipid arc and calcium depht were significantly lower in female patients than in male ones (118.0° ± 79.9° vs. 135.5° ± 77.9°; p=0.011; and 52.7 µm ± 79.2 µm vs. 72.3 µm ± 93.5 µm; p=0.007) while fibrous cap tended to be thicker (108.2 µm ± 70.4 µm vs. 96.2 µm ± 72.9 µm; p=0.055). Healed plaques were significantly more frequent in female patients than in male patients (51.9% vs 34.6%; p = 0.027). The prevalence of fibrous plaque, thrombi, neovascularization, diffuse calcifications and spotty calcification was not different between the two groups. Conclusion Females have a distinct atherosclerotic phenotype and healing capacity compared with male patients, including lower prevalence of lipid-rich plaque, cholesterol crystals and plaque ruptures and higher prevalence of healed plaques in non-culprit coronary lesions.