Background and purpose: GPR55 is activated by the endogenous lipid lysophosphatidylinositol, but also sensitive to cannabinoids and antagonized by cannabidiol. While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of GPR55 herein is poorly understood. Thus, we investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Experimental approach: Following baseline characterization, permanent MI was induced in global GPR55-/- and wildtype (WT) mice as well as in bone marrow chimaeras with sole haema-topoietic GPR55 depletion. Sarcomere length was measured in isolated adult, unstressed GPR55-/- and WT left ventricular (LV) myocytes. Key results: GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and an immune profile resembling stretch-induced inflammation. While infarct size and myeloid cell infiltration were unaffected by the lack of GPR55, chemokine induction was prolonged until day 3 post-MI. Additionally, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of ex-tracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. Conclusions and implications: GPR55 regulates cardiac homeostasis and ischaemia respons-es by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, hypertrophy and maladaptive remodelling. While patients might benefit from GPR55 stimulation post-MI, consumption of GPR55 antagonist cannabidiol should be carefully considered in view of potential adverse cardiac effects.