Background: Various cell types undergo activation and stress during atherosclerosis resulting in the development of acute myocardial infarction (AMI) in coronary artery disease (CAD). Major histocompatibility complex class I related chain A and B (MICA/B) can be expressed on the surface of activated and stressed cells and released into blood circulation in several forms including microparticles (MICA/B⁺ MPs) from various cell types. We aimed to investigate the association of these MICA/B⁺ MPs with the presence of AMI. Fifty-one AMI and 46 age-matched control subjects were recruited. Methods: Levels of MICA/B⁺ MPs derived from various parent cells including endothelial cells, platelets, monocytes, neutrophils, and T lymphocytes were determined by flow cytometry. Results: The levels and proportion of MICA/B⁺ MPs from all types of cell origin were significantly increased in AMI patients compared to those of the controls. A multivariate regression model showed an independent association between MICA/B⁺ MPs and AMI (OR = 11.6; 95% CI = 2.8, 47.3). Interestingly, based on the disease severity, we found that the levels of MICA/B⁺ MPs were significantly elevated in the ST-segment elevation myocardial infarction (STEMI) compared to the non-STEMI (NSTEMI) patients. Moreover, an independent association of MICA/B⁺ MPs with the occurrence of STEMI was also demonstrated (OR = 4.1; 95% CI = 1.5, 16.7). Conclusions: These results suggest that MICA/B⁺ MPs are associated with AMI and disease severity. They may act as mediators contributing to the pathological process of AMI. Alternatively, they are the results of various cell activations contributing to AMI.