Heart-specific antibodies have been widely associated with myocardial infarction (MI). However, it remains unclear whether autoantibodies mediate disease progression or are a byproduct of cardiac injury. To disambiguate the role of immunoglobulins in MI, we characterized the development of ischemic heart failure (HF) in agammaglobulinemic mice (AIDμS). While these animals can produce functional B-cells, they cannot synthesize secretory IgM (μS) or perform immunoglobulin class-switching (AID), leading to complete antibody deficiency. Agammaglobulinemia did not affect overall post-MI survival but resulted in a significant reduction in infarct size. Echocardiographic analyses showed that compared to the WT infarcted controls, the AIDμS mice exhibited improved cardiac function and reduced remodeling at day 56 post-MI. These differences remained significant even after animals with matched infarct sizes were compared. Infarcted AIDμS mice also showed reduced myocardial expression levels of transcripts known to promote adverse remodeling, such as Mmp9, Col1a1, Col3a1, and Il6. An unbiased screening of the heart-reactivity potential in the plasma of WT MI animals revealed the presence of antibodies that target the myocardial scar and collagenase-sensitive epitopes. Moreover, we found that IgG accumulated within the scar tissues of infarcted mice and remained in close proximity with cells expressing Fcγ receptors (CD16/32, FcγR), suggesting the existence of an in situ IgG-Fcγ receptor axis. Collectively, our study results confirm that antibodies contribute to ischemic HF progression and provide novel insights into the mechanisms underlying this phenomenon.