OBJECTIVES:  To compare palbociclib + letrozole and palbociclib + fulvestrant with chemotherapies in postmenopausal women with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced/ metastatic breast cancer (ABC/MBC) who had no prior systemic treatment for advanced disease (first-line) or whose disease had progressed after prior endocrine therapy or chemotherapy (second-line). METHODS:  A systematic search identified randomized controlled trials (RCTs) published from January 2000 to January 2016, comparing endocrine-based therapies, chemotherapies, and/or chemotherapies + biological therapies in the first- and second-line treatment of postmenopausal women with HR+/HER2- ABC/MBC. Outcomes of interest were progression-free survival (PFS)/time to progression (TTP) and overall survival ([OS], first line only). OS was not included for palbociclib + fulvestrant due to immature data. Bayesian network meta-analyses (NMAs) and pairwise meta-analyses were conducted to pool RCT results where appropriate. Heterogeneity and inconsistency were assessed. RESULTS:  Sixty RCTs met eligibility criteria and were stratified by line of therapy and outcome. In the first-line, palbociclib + letrozole showed statistically significant improvements in PFS/TTP versus capecitabine (HR=0.28 [0.11-0.72]) and mitoxantrone (HR=0.28 [0.13-0.61]), and trended towards improvements versus paclitaxel (HR=0.59 [0.19-1.96]), docetaxel (HR=0.51 [0.14-2.03]) and other mono or combination chemotherapies (HRs ranging from 0.33 to 0.99). OS results trended in favor of palbociclib + letrozole, but were not statistically significant. Similarly, in the second-line, palbociclib + fulvestrant showed statistically significant improvements in PFS/TTP versus capecitabine (HR=0.28 [0.13-0.65]), mitoxantrone (HR=0.26 [0.12-0.53]), and liposomal doxorubicin (HR=0.19 [0.07-0.50]), and trended towards improvements versus paclitaxel (HR=0.48 [0.16-1.44]), docetaxel (HR=0.71 [0.24-2.13]) and other mono or combination chemotherapies (HRs ranging from 0.23 to 0.89). NMA findings aligned with direct evidence and were robust to sensitivity analyses to adjust for heterogeneity. CONCLUSIONS:  Palbociclib + letrozole and palbociclib + fulvestrant demonstrate trends in incremental efficacy compared with chemotherapies for first- and second-line treatment of HR+/HER2- ABC/MBC.