Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate repair. However, exaggerated and/or persistent inflammation compromises healing, which may be counteracted by regulatory immune mechanisms. A key regulatory factor in an inflammatory response is the anti-inflammatory cytokine IL-10, which can be produced by a number of immune cells including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found abundant IL-10-producing B cells in PATs under homeostatic conditions, with the majority of them bearing cell surface CD5 (CD5+ B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters (FALCs). The cytokine IL-33 was preferentially expressed in PATs under homeostatic conditions and contributed to enrichment of IL-10-producing CD5+ B cells in PATs. CD5+ B cells expanded in PATs following MI, and accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function after MI, exacerbated myocardial injury, and delayed resolution of inflammation. These findings reveal a significant contribution of IL-10-producing B cells to the anti-inflammatory mechanism that terminates MI-induced inflammation, and identify these cells as novel therapeutic targets to improve the outcome of MI. Significance StatementMyocardial infarction (MI) remains a leading cause of mortality and morbidity worldwide. Although it is now recognized that a balanced and timely terminated pro-inflammatory response following acute MI is essential in promoting tissue repair, the underlying regulatory mechanisms are poorly defined. In this report, we show that IL-10-producing B cells in mice 1) are enriched in pericardial adipose tissues (PATs) and influenced by cytokine IL-33 under homeostatic conditions; 2) expand in PATs following MI and accumulate in the infarcted heart during the resolution of MI-induced inflammation; and 3) facilitate resolution of inflammation and reduce myocardial injury to preserve cardiac function after MI. These findings identify IL-10-producing B cells as novel therapeutic targets to improve the outcome of MI.