Background: Palbociclib has been approved as the first CDK4/6 inhibitor in China since 2018. This study aimed to collect real-world data for retrospective analysis of the clinical outcomes and potential clinical and genetic risk factors for Palbociclib plus ET. Methods: Data of 194 HR+HER2- ABC patients who received Palbociclib plus ET between May 2018 and Dec 2020 were collected from the electronic medical record system of seven cancer centers across China. Cox regression models and bioinformatic analysis were conducted to investigate the risk factors. Results: In total, 194 patients were included in the study. Among them, 138 patients discontinued Palbociclib plus ET due to disease progression (130 patients), financial inability (5 patients), or intolerable adverse reactions (3 patients) as of the observation endpoint. With a median follow-up period of 22.4 months, the median progression-free survival (mPFS) was 12.3 months, the median time to failure (mTTF) was 11.8 months, and the median overall survival (mOS) was 35.5 months. Moreover, the 1-year PFS, TTF and OS rates were 50.8%, 49.0% and 87.6%, respectively. Of the 155 with measurable disease, the objective response rate (ORR) was 27.1%, the disease control rate (DCR) was 71.6% and the clinical benefit rate (CBR) was 81.3%. KM curves showed that first-line users had the mPFS of 19.0 months, which was significantly longer than the second-line users and the third (or higher) line users (mPFS = 10.7 and 7.2 months, p＜0.0001). Multivariate Cox regression analysis revealed several clinical features as risk factors, whereas liver metastasis was a significant risk factor for poor PFS and OS (HR = 1.993, [95%CI, 1.243-3.195], p = 0.004; HR = 2.345, [95%CI, 1.089-5.049, p = 0.029). Central nervous system (CNS) metastasis was an independent risk factor for poor OS (HR = 2.658, [95%CI, 1.152-6.136], p = 0.022). Response to CR/PR was a significant protective factor for PFS (HR = 0.289, [95%CI, 1.161-0.519], p＜0.001) but not for OS. Postmenopausal patients had a higher PFS risk than premenopausal patients (HR = 1.549, [95%CI, 1.007-2.382], p = 0.046). Seven patients received circulating tumor DNA (ctDNA) testing at the baseline and after disease progression, which showed that the mutation frequencies of FGFR1, ARID1A, ATRX, CHD4, FAT1, and PTEN increased significantly after disease progression. Conclusions: Treatment with Palbociclib plus ET exhibited favorable efficacy for HR+HER2– ABC in Chinese real-world practices, especially for non-liver, non-CNS metastasis or premenopausal patients. Early-line treatment yielded more durable benefits, and response to CR/PR indicated a better PFS prognosis. Mutations in FGFR1, ARID1A, ATRX, CHD4, FAT1, and PTEN might be associated with resistance to the combination therapy.