To investigate the effect of interleukin-6 (IL-6) gene knockout on apoptosis of myocardial cells in mice with Coxsackievirus B3 (CVB3)-induced dilated cardiomyopathy (DCM) and its potential mechanism, so as to provide certain references for the clinical prevention and treatment of DCM.A total of 40 male C57 mice were randomly divided into Sham group (n=20) and DCM group (n=20) using a random number table. Another 20 mice with IL-6 gene knockout were enrolled into DCM+IL-6 KO group (n=20). The DCM model was established via CVB3 repeated incremental infection. After 9 months, the heart weight/body weight (HW/BW) ratio of mice in each group was detected. The ejection fraction [EF (%)] and fraction shortening [FS (%)] of mice in each group were detected via two-dimensional ultrasonography. The cross-sectional area and pathological changes in myocardial cells in the heart in each group were determined using hematoxylin-eosin (HE) staining. The collagen content in myocardial tissues in each group was detected via Masson staining and picrosirius red (PSR) staining, and the expressions of Collagen I and Collagen III in myocardial tissues in each group were detected via immunohistochemistry. In addition, the myocardial apoptosis in myocardial tissues in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Finally, the protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and total STAT3 (t-STAT3) were detected via Western blotting.The expression of IL-6 messenger ribonucleic acids (mRNAs) in myocardial tissues in DCM group was significantly increased compared with that in Sham group (p0.05). After IL-6 knockout, the HW/BW ratio of DCM mice significantly declined (p0.05), and the cross-sectional area of myocardial cells was significantly reduced (p0.05). According to the results of echocardiography, the cardiac function of mice in DCM+IL-6 KO group was significantly superior to that in DCM group, manifested as the significant increase in FS (%) and EF (%) (p0.05). The results of Masson staining, PSR staining, and immunohistochemical staining showed that IL-6 knockout could reduce the collagen content and Collagen I and Collagen III expressions in myocardial tissues of DCM mice (p0.05). Furthermore, it was found via TUNEL staining that the number of apoptotic myocardial cells in DCM+IL-6 KO group was markedly smaller than that in DCM group (p0.05). At the same time, the Bax/Bcl-2 ratio in myocardial tissues in DCM+IL-6 KO group was lower (p0.05). Finally, the results of Western blotting revealed that DCM+IL-6 KO group had a lower phosphorylation level of STAT3 than DCM group (p0.05).Inhibiting IL-6 gene may improve the DCM-induced myocardial remodeling through reducing myocardial apoptosis.