BACKGROUND: Layered plaque, a signature of previous plaque disruption, is a known predictor of rapid plaque progression. Layered plaque can be identified in vivo by optical coherence tomography. Studies have reported differences in plaque burden between women and men, but sex differences in the pattern of layered plaque are unknown. METHODS: Preintervention optical coherence tomography images of 533 patients with chronic coronary syndromes were analyzed. Detailed plaque characteristics of layered and nonlayered plaques of the target lesion were compared between men and women. RESULTS: The prevalence of layered plaque was similar between men (N=418) and women (N=115; 55% versus 54%; P =0.832). In men, more features of plaque vulnerability were identified in layered plaque than in nonlayered plaque: lipid plaque (87% versus 69%; P <0.001), macrophages (69% versus 56%; P =0.007), microvessels (72% versus 39%; P <0.001), and cholesterol crystals (49% versus 30%; P <0.001). No difference in plaque vulnerability between layered and nonlayered plaques was observed in women. Layered plaque in men had more features consistent with previous plaque rupture than in women: interrupted pattern (74% versus 52%; P <0.001) and a greater layer index (1198 [781–1835] versus 943 [624–1477]; P <0.001). CONCLUSIONS: In men, layered plaques exhibit more features of vascular inflammation and vulnerability as well as evidence of previous plaque rupture, compared with nonlayered plaques, whereas in women, no difference was observed between layered and nonlayered plaques. Vascular inflammation (plaque rupture) may be the predominant mechanism of layered plaque in men, whereas a less inflammatory mechanism may play a key role in women. REGISTRATION: URL: http://www.clinicaltrials.gov ; Unique Identifier: NCT01110538, NCT04523194