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Abstract Background A sizeable proportion of patients with Acute Coronary Syndromes (ACS) shows a unique adaptive immune system profile, associated to a worse outcome, characterized by higher CD4+CD28null T-cells, lower regulatory T-cells (Treg) and increased CD4+CD28null/Treg ratio. We sought to investigate the correlation between CD4+CD28null T-cells, Treg, CD4+CD28null/Treg ratio and plaque phenotype as assessed by Optical Coherence Tomography (OCT). Methods Peripheral blood mononuclear cells (PBMC) were collected from 30 Non-ST Elevation Myocardial Infarction (NSTEMI) patients, sub-grouped according to OCT analysis of culprit lesions into two cohorts: Ruptured Fibrous Cap (NSTEMI-RFC, n = 12) and Intact Fibrous Cap (NSTEMI-IFC, n = 18). Stable Angina patients (SA, n = 18) were used as controls. We examined the frequency of CD4+CD28null and Treg (defined as CD4+CD25highCD127lowFoxp3+ T-cells) by flow-cytometry. Results CD4+CD28null frequency (median, range) was significantly higher in NSTEMI-RFC patients (17.3%, 12.5–33.8) as compared with NSTEMI-IFC (3.8%, 0.3–14.1) and SA (3%, 0.6–17.7) (P < 0.001 for all comparisons). We also found a higher CD4+CD28null/Treg ratio in NSTEMI-RFC patients (6.6%, 3.7–13.9) than in NSTEMI-IFC (1.6%, 0.3–5.2) and SA (1.2%, 0.3–8.7) (P < 0.001 for all comparisons). Finally, there was an inverse correlation between CD4+CD28null/Treg ratio and cap-thickness (R = −0.44; P = 0.002). Conclusion Patients with NSTEMI presenting with RFC as culprit lesion at OCT evaluation have a specific perturbation of adaptive immunity, mostly involving CD4+CD28null T- cells and Tregs, as compared with patients with IFC and SA. This specific imbalance of T-cells might play a key role in fibrous cap thinning, predisposing atherosclerotic plaque to rupture. Highlights • Plaque rupture at OCT evaluation is associated to a specific adaptive immune system signature. • A deeper perturbation of adaptive immunity might be involved in fibrous cap thinning. • Molecular and morphological plaque phenotyping might be a new frontier for personalized medicine. [ABSTRACT FROM AUTHOR]