Background Several endocrine therapies are available for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer (ABC). Given the absence of direct comparisons between fulvestrant and cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with aromatase inhibitors (AIs), which are both used as standard first-line treatments for ABC, an indirect comparison using a network meta-analysis may be advantageous for decision making. Objective We performed a network meta-analysis to compare the efficacies of fulvestrant and CDK4/6is plus AIs as the first-line treatment of postmenopausal breast cancer patients. Patients and Methods In order to compare these treatments, we searched the PubMed, Cochrane Library, and EMBASE databases for randomized controlled trials of first-line endocrine treatment for advanced or metastatic breast cancer until October 2018. We included a total of 11 eligible trials with 5448 patients. The hazard ratios (HRs) for the efficacies of the different treatments were used as inputs in the network meta-analysis. Results In the overall analysis, CDK4/6is plus AIs, including palbociclib plus letrozole, ribociclib plus letrozole, and abemaciclib plus nonsteroidal AI (letrozole or anastrozole), are all superior to 500mg fulvestrant (HR=0.50, 95% confidence interval [CI] 0.37-0.68; HR=0.50, 95% CI 0.35-0.71; and HR=0.49, 95% CI 0.34-0.71; respectively). Conclusions Within the limitations of this network meta-analysis, the comparison indicates that CDK4/6is plus AIs might represent a better option for HR+ABC as a first-line endocrine treatment compared with fulvestrant.