While there is general agreement on the favorable impact of immunosuppression in eosinophilic, granulomatous, giant cell and lymphocytic myocarditis and with inflammatory myocardial disease associated with connective tissue disorders or with rejection of a transplanted heart, its therapeutic role in the treatment of lymphocytic inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant (≥ 10% left ventricular ejection fraction) clinical benefit in 90% of patients with virus-negative ICM and no cardiac impairment in 85% of patients with virus-positive ICM following immunosuppression. Some studies identified cardiomyocyte HLA up-regulation as an additional indicator of ICM susceptibility to immunosuppressive therapy. Recently in a single-center randomized prospective double-blind trial using a combination of prednisone (1 mg/kg per day for 4 weeks followed by 0.33 mg/kg per day for 5 months) and azathioprine (2 mg/kg per day for 6 months) in addition to supportive treatment in 85 virus-negative ICM patients, a significant improvement of left ventricular ejection fraction and a significant reduction of left ventricular dimensions in 88% of 43 treated patients was reported when compared to 42 patients receiving placebo who showed a cardiac impairment initially in 83% of cases (TIMIC study). These data confirm the efficacy of immunosuppression in virus-negative ICM. The lack of response in 12% of cases suggests that the missing response might be due to the presence of viruses which were not screened for or to mechanisms of damage and inflammation not susceptible to immunosuppression. The recovery of cardiac function in responders to immunosuppression was associated with the inhibition of cardiomyocyte death, an increase of cell proliferation and with newly synthesized contractile material.