Background: One of the major dose-limiting toxicities of anthracyclines is cardiotoxicity due to irreversible cardiomyopathy. Whether cisplatin-based treatment induces cardiotoxicity in the short term, especially in non-small cell lung cancer (NSCLC) patients with cardiovascular comorbidity, has not been studied previously. The aim of this study was to evaluate cardiotoxicity in advanced NSCLC patients receiving cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) as first-line treatment. Patients and Methods: Patients were randomised to receive gemcitabine 1125 mg/m(2) (days 1 and 8) plus either cisplatin 80 mg/m(2) (day 2) or epirubicin 100 mg/m(2) (day 1) every 3 weeks for a maximum of 5 cycles. Patients had to have a left ventricular ejection fraction (LVEF) > 45%, measured by multiple gated acquisition (MUGA) scan. A second MUGA scan was performed 12 weeks after the end of treatment. Results: Sixty-nine patients were included. The mean total dose of cisplatin was 349 mg/m(2) and of epirubicin 452 mg/m(2). The mean difference in decline in LVEF from baseline was 2% in the CG arm versus 6% in the EG arm (p = 0.016). Clinically evident cardiac failure was not observed during 12 months follow-up. No correlation was found with total drug doses administered. In patients with a history of cardiac disease a trend towards a higher decrease in LVEF was observed. Conclusion: Although in the EG arm the LVEF significantly declined and in the CG arm a trend for LVEF to decline was observed, the risk of cardiac failure is limited in advanced NSCLC patients.