Background: The role of the immune system in the context of acute myocardial infarction (MI), and its response to such event are poorly characterized, but is thought to be an important driver of myocardial remodeling, thromboinflammation, and exacerbation of atherosclerosis - triggering recurrent cardiovascular events. So far, anti-inflammatory approaches drugs have shown promising effects on the prevention of recurrent cardiovascular events or myocardial salvage after myocardial infarction. However, they broadly impair the immune system and some are associated with increased infectious side effects. Therefore, a more detailed understanding of the immune response to myocardial infarction is needed to tailor anti-inflammatory therapeutic approaches in MI patients. Methods: To gain such detailed longitudinal understanding of the immune response in ST-elevated myocardial infarction (STEMI) patients, we compared peripheral blood mononuclear cell (PBMCs) single-cell RNA-sequencing (scRNA-seq) expression and plasma protein profiles over time and in comparison to age- and sex-balanced controls in 38 STEMI patients at hospital admission, 24 hours (acute phase) and 6-8 weeks (chronic phase) after STEMI. Results: In total, 95,995 diseased and 33,878 control PBMCs were analyzed. Compared to controls, we observed a relative increase in the number of classical monocytes and a decrease in the number of CD56dim natural killer cells in STEMI patients at admission, and these differences persisted until 24 hours after STEMI. The monocytes also showed the largest gene expression changes in STEMI patients compared to controls, and in STEMI patients over time. These were associated with changes in the activity of toll-like receptors, IFN and IL-1 signaling. Subsequent differential cell-cell communication analysis suggested that these monocytes are mainly involved in the outgoing differential communication in the first 24h after a STEMI, whereas in the next 6-8 weeks they become mostly involved in the incoming differential communication. Finally, a targeted protein cardiovascular biomarker panel revealed 33 out of 92 plasma proteins to be changed during the acute and/or chronic phase after STEMI. Interestingly, the plasma levels of three of these proteins were found to be affected by genetic variation, disease status and time after STEMI. Indicating the importance of taking all these aspects into consideration when defining potential future therapies. Conclusions: Altogether, our analyses have revealed the immunological pathways that are disturbed upon MI, and in which cell type and during which stage of the disease. Additionally, we also provide insights in which patients are expected to benefit most from anti-inflammatory treatments, by identifying the genetic variants and disease stage at which these variants affect the outcome of these (drug-targeted) pathways. These findings advance our knowledge of the immune response after MI and provide further guidance for future therapeutic studies.