Estimate the cost-effectiveness and budget impact of fulvestrant for locally advanced or metastatic breast cancer in postmenopausal women who have not received prior endocrine therapy in comparison with currently used aromatase inhibitors (AI) and cyclin-dependent kinase (CDK) 4/6 inhibitors in the public health system in Mexico. Cost-effectiveness and budget impact analyses were conducted from the perspective of the public health system in Mexico, as payer. The interventions included fulvestrant, anastrozole, letrozole, exemestane, tamoxifen, palbociclib-letrozole and ribociclib-letrozole. Due to the lack of head to head trials, a network metanalysis was performed. The decision model was a partitioned survival model with 3 health states: progression free survival, post-progression survival and death. A 4-week cycle length over a 20-year time horizon was applied to the model. Only direct medical costs were included. All costs are expressed in 2018 US dollars. Effectiveness was measured as expected life years. A discount rate of 5% was used. Probabilistic and deterministic sensitivity analyses were also conducted. The budget impact analysis comprehended a 5-year period with a penetration rate of fulvestrant ranging from 10% to 30%. Fulvestrant was associated with the highest life expectation within monotherapies, but also the highest cost, resulting in ICERs between $13,277 (vs exemestane) and $25,338 (vs letrozole). The CDK 4/6-letrozole schemes had a higher effectiveness than fulvestrant, but increased the cost to almost the double, with ICERs of $79,574 and $273,416. Sensitivity analyses demonstrated model results are robust to uncertainty of model inputs. According to the penetration rate of fulvestrant, the net impact in the health federal budget would be $13.68 million. This analysis suggests that, according to internationally accepted criteria, fulvestrant constitutes a cost-effective alternative for locally advanced or metastatic breast cancer in postmenopausal women who have not received prior endocrine therapy, with a low budget impact.