Ribociclib has provided significant improvements in progression-free survival (PFS) and overall survival (OS) of postmenopausal patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). However, given the high cost of ribociclib, its value must be evaluated based on cost-effectiveness. Thus, we aimed to explore the cost-effectiveness of ribociclib for postmenopausal patients with HR-positive and HER2-negative ABC. A comprehensive Markov model was developed to estimate the cost-effectiveness of ribociclib plus fulvestrant versus placebo plus fulvestrant as first-line treatment for HR-positive, HER2-negative ABC. Variables were estimated based on data from the randomized Phase III MONALEESA-3 trial. Ten-year values were estimated for quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Direct treatment costs were estimated from the perspective of a United States payer. One-way and probabilistic sensitivity analyses were conducted to confirm the model's robustness. Ribociclib plus fulvestrant increased the treatment cost by $382,172 and provided 0.47 QALYs, relative to fulvestrant alone, which corresponded to an ICER of $813,132 per QALY. Sensitivity analyses revealed that ribociclib was unlikely to be cost-effective even under the most favorable assumptions. When the cost of ribociclib was <$1,384, there was a >50% chance of cost-effectiveness at a willingness-to-pay threshold of $150,000/QALY. Subgroup analyses also confirmed that ribociclib was not cost-effective. At current drug prices in the United States, ribociclib is unlikely to be cost-effective for treating postmenopausal patients with HR-positive HER2-negative ABC. Despite the clinical benefits of ribociclib, its cost would need to decrease to provide more favorable economic outcomes.