© 2016 The Authors Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3 months of age. Compared to wild type (WT) mice, DCM mice exhibited significantly decreased fractional shortening (36.4 ± 2% vs. 15.5 ± 1.0%, p < 0.0001) and significantly increased spleen weight (5.3 ± 0.3 vs. 7.2 ± 0.4 mg/mm, p = 0.002). Intriguingly, flow cytometry analysis revealed a significant increase in total (CD45+ CD11b+ Ly6C− MHCII+ F480+) macrophages (6.5 ± 1.4% vs. 14.8 ± 1.4%, p = 0.002) and classically activated (CD45+ CD11b+ Ly6C− MHCII+ F480+ CD206−) proinflammatory (M1) macrophages (3.4 ± 0.8% vs. 10.3 ± 1.2%, p = 0.0009) in DCM hearts as compared with WT hearts. These results were further confirmed by immunofluorescence analysis of heart tissue sections. Splenic red pulp (CD11b+ Ly6C+ MHCIIlowF480hi) macrophages were significantly elevated (1.3 ± 0.1% vs. 2.4 ± 0.1%, p = 0.0001) in DCM compared to WT animals. Serum cytokine analysis in DCM animals exhibited a significant increase (0.65 ± 0.2 vs. 2.175 ± 0.5 pg/mL, p = 0.02) in interleukin (IL)-6 compared to WT animals. Furthermore, RNA-seq analysis revealed the upregulation of inflammatory pathways in the DCM hearts. Together, these data indicate a robust proinflammatory response in DCM hearts, likely in response to cellular damage triggered by MYBPC3 mutation and resultant contractile dysfunction.