Abstract Background We aimed to evaluate the effect of prophylactic nebivolol use on prevention of antracycline-induced cardiotoxicity in breast cancer patients. Methods In this small, prospective, double-blind study, we randomly assigned 45 consecutive patients with breast cancer and planned chemotheraphy to receive nebivolol 5 mg daily (n = 27) or placebo (n = 18). Echocardiographic measurements and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were obtained at baseline and at 6-month of chemotherapy. Results Both studied groups had comparable echocardiographic variables and NT-pro-BNP levels at baseline. At 6-month, the left ventricular (LV) end-systolic and end-diastolic diameters increased in the placebo group (LVESD: 29.7 ± 3.4 to 33.4 ± 4.5 mm; LVEDD: 47.2 ± 3.8 to 52.0 ± 4.6 mm, p = 0.01 for both) but remained unchanged in the nebivolol group (LVESD: 30.4 ± 3.5 to 31.0 ± 3.6 mm, p = 0.20; LVEDD: 47.0 ± 4.4 to 47.1 ± 4.0 mm, p = 0.93). The placebo group also had lower LVEF than the nebivolol group (57.5 ± 5.6% vs. 63.8 ± 3.9%, p = 0.01) at 6-month. NT-pro-BNP level remained static in the nebivolol group (147 ± 57 to 152 ± 69 pmol/l, p = 0.77) while it increased in the placebo group (144 ± 66 to 204 ± 73 pmol/l, p = 0.01). Conclusions Prophylactic use of nebivolol treatment may protect the myocardium against antracycline-induced cardiotoxicity in breast cancer patients.