Despite numerous case reports, the incidence of a secondary diagnosis of head and neck squamous cell carcinoma (HNC) following pegylated liposomal doxorubicin (PLD) treatment is unknown. Computerized pharmacy records were searched at a large, multi-center healthcare system for patients who received PLD. Electronic medical records were searched to identify the patient's age at treatment initiation of PLD, diagnosis for which they were treated with PLD, number of courses and total cumulative dose of PLD (TCDPLD) and secondary malignancies. Published PLD associated HNC was utilized to determine the lowest and median TCDPLD doses associated with HNC. One thousand two hundred ninety eligible patients who had been treated with PLD were identified. The lowest TCDPLD associated HNC in the literature is 405 mg/m2. In our healthcare system, 275 patients received more than 400 mg/m2 yielding a risk of 0.004%. One hundred fifty-one patients received the lowest TCDPLD associated with HNC cancer in our series which was 640 mg/m2 yielding a risk of 0.007%. Four of 30 patients (13.3%) developed HNC who received the median TCDPLD associated with HNC in the literature of 1440 mg/m2. Five of 20 patients (25%) receiving 1650 mg/m2 developed HNC in our healthcare system. Prolonged therapy with PLD is associated with an increased risk of HNC. This risk appears to be related to the cumulative dose varying from 0.004 to 13.3% at the lowest and median TCDPLD of reported cases in the literature, respectively. Oncologists need to be aware of this risk and to screen patients appropriately.