Background: Anthracyclines play an important role in the treatment of breast cancer (BC) while cardiotoxicity, a serious side effect, limits the clinical application. Pegylated liposomal doxorubicin (PLD) is a new dosage form of doxorubicin encapsulated in liposomes, which can reduce the plasma free level of doxorubicin and drug to normal tissue delivery, thereby reducing cardiotoxicity. The aim of this study was to evaluate the cardiac safety and efficacy of PLD compared with doxorubicin as adjuvant therapy in breast cancer patients. Methods: This is an open-label, randomized trial involving patients with operable breast cancer who were at high risk of recurrence after radical sugery (NCT03949634). Patients were randomized (1:1) to receive adjuvant PLD or doxorubicin (A) and cyclophosphamide followed by taxanes ± trastuzumab. The primary endpoint was cardiotoxicity, which was defined as congestive heart failure (CHF) with clinical symptoms, or no symptoms but with an abnormal left ventricular ejection fraction (LVEF). Secondary endpoints included 5-year disease-free survival (DFS) rate, 5-year overall survival (OS) rate and safety. Results: Between November 2017 and September 2019, 247 patients were randomized and received study treatment (PLD arm, 131; A arm, 116). The median age was 49 years (range, 26-67) in PLD arm and 48 years (range, 25-70) in A arm. The pathological stages were 18.3% stage I, 58.0% stage II, and 22.1% stage III in PLD arm, while those of A arm were 20.7% stage I, 59.5% stage II, and 19.8% stage III. The median follow-up time was 43.0 months. The incidence of abnormal LVEF was 0 in the PLD arm and 1.7% the A arm (P = 0.220). The incidence of CHF was 0 in the PLD arm and 0.9% the A arm (P = 0.470). Survival data analysis is immature. The exploratory analysis of cardiac-related biomarkers showed that the incidence of high-sensitivity cardiac troponin-T (hs-cTnT) was lower in PLD arm than in A arm (3.8% vs. 30.2%, P < 0.001). Grade 3/4 adverse events (AEs) occurred in 42.7% patients in PLD arm and in 61.2% patients in A arm. The most common grade 3/4 AEs in PLD arm and A arm included neutropenia (34.4% vs. 55.2%), leukopenia (30.5% vs. 39.7%), and hand-foot syndrome (4.6% vs. 0.0%). Conclusions: Hs-cTnT elevation may have a role in the AE prediction of antharcycline. PLD usage may present lower incidence of cardiotoxicity than doxorubicin in the adjuvant treatment of patients with early-stage breast cancer. Clinical trial information: NCT03949634.