The ability of trimetazidine (2,3,4, trimethoxybenzylpiperazine dihydrochloride, TMZ) to protect the myocardium against anthracycline (ANT)-induced cardiotoxicity during chemotherapy has been evaluated in female patients with breast cancer. A clinical trial was conducted in 61 patients subdivided into three groups: group 1 (n = 15, G1 ) treated with standard ANT protocol and cardioprotection by dexrazoxane (DEX) plus TMZ (60 mg, daily dose); group 2 (n = 22, G2) treated with ANT and cardioprotection by TMZ only; and group 3 (n = 24, G3) scheduled to receive ANT therapy and DEX. All the patients submitted to an echocardiographic evaluation of diastolic function (E wave velocity, A wave velocity, isovolumetric relaxation time [IVRT], deceleration time [DT]) at enrollment (T0), at T1 time, at T2 time, and at T3 time. After a 12-month follow-up period, the patients showed a good conservation of diastolic function both in G1 and G2 groups. No statistically significant difference was observed in E wave and A wave velocity and E/A ratio after ANT treatment. TMZ produced a cardioprotective effect, comparable to DEX protection, against subacute and chronic subclinical cardiotoxicity with no significant changes in diastolic function after 1 year of follow-up.